wpt paris

Cancer is considered the second leading cause of death worldwide and in 2018 it was responsible for approximately 9.6 million deaths. Globally, about one in six deaths are caused by cancer. A strong correlation was found between diabetes mellitus and carcinogenesis with the most evident correlation was with type 2 diabetes mellitus (T2DM). Research has proven that elevated blood glucose levels take part in cell proliferation and cancer cell progression. However, limited studies were conducted to evaluate the efficiency of conventional therapies in diabetic cancer patients. In this review, the correlation between cancer and diabetes will be discussed and the mechanisms by which the two diseases interact with each other, as well as the therapeutics challenges in treating patients with diabetes and cancer with possible solutions to overcome these challenges. Natural products targeting both diseases were discussed with detailed mechanisms of action. This review will provide a solid base for researchers and physicians to test natural products as adjuvant alternative therapies to treat cancer in diabetic patients. clear

You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader.

Find support for a specific problem in the support section of our website.

Get Support Please let us know what you think of our products and services.

Give Feedback Visit our dedicated information section to learn more about MDPI.

Get Information clear by Wamidh H. TalibWamidh H. Talib SciProfiles Scilit Preprints.org Google Scholar 1,*, Asma Ismail MahmodAsma Ismail Mahmod SciProfiles Scilit Preprints.org Google Scholar 1, Sara Feras. AbuarabSara Feras. Abuarab SciProfiles Scilit Preprints.org Google Scholar 1, Eliza HasenEliza Hasen SciProfiles Scilit Preprints.org Google Scholar 1, Amer A. MunaimAmer A. Munaim SciProfiles Scilit Preprints.org Google Scholar 1, Shatha Khaled HaifShatha Khaled Haif SciProfiles Scilit Preprints.org Google Scholar 1, Amani Marwan AyyashAmani Marwan Ayyash SciProfiles Scilit Preprints.org Google Scholar 1, Samar KhaterSamar Khater SciProfiles Scilit Preprints.org Google Scholar 1, Intisar Hadi AL-YasariIntisar Hadi AL-Yasari SciProfiles Scilit Preprints.org Google Scholar 2 and Lina T. Al KuryLina T. Al Kury SciProfiles Scilit Preprints.org Google Scholar 31Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan2Department of Genetic Engineering, College of Biotechnology, Al-Qasim Green University, Babylon 00964, Iraq3Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, United Arab Emirates*Author to whom correspondence should be addressed. Molecules2021, 26(8), 2179; https://doi.org/10.3390/molecules26082179 Submission received: 13 March 2021 / Revised: 2 April 2021 / Accepted: 6 April 2021 / Published: 10 April 2021 (This article belongs to the Special Issue Natural Products for the Treatment of Diabetes and Obesity) Download keyboard_arrow_downDownload PDFDownload PDF with CoverDownload XMLDownload EpubBrowse FiguresVersions Notes

Abstract

:Cancer is considered the second leading cause of death worldwide and in 2018 it was responsible for approximately 9.6 million deaths. Globally, about one in six deaths are caused by cancer. A strong correlation was found between diabetes mellitus and carcinogenesis with the most evident correlation was with type 2 diabetes mellitus (T2DM). Research has proven that elevated blood glucose levels take part in cell proliferation and cancer cell progression. However, limited studies were conducted to evaluate the efficiency of conventional therapies in diabetic cancer patients. In this review, the correlation between cancer and diabetes will be discussed and the mechanisms by which the two diseases interact with each other, as well as the therapeutics challenges in treating patients with diabetes and cancer with possible solutions to overcome these challenges. Natural products targeting both diseases were discussed with detailed mechanisms of action. This review will provide a solid base for researchers and physicians to test natural products as adjuvant alternative therapies to treat cancer in diabetic patients.Keywords: hyperglycemia; cancer; Warburg effect; alternative therapies; obesity; metabolic syndrome; hyperinsulinemia; cancer metabolism; oxidative stress; natural products : Cancer is considered the second leading cause of death worldwide and in 2018 it was responsible for approximately 9.6 million deaths. Globally, about one in six deaths are caused by cancer. A strong correlation was found between diabetes mellitus and carcinogenesis with the most evident correlation was with type 2 diabetes mellitus (T2DM). Research has proven that elevated blood glucose levels take part in cell proliferation and cancer cell progression. However, limited studies were conducted to evaluate the efficiency of conventional therapies in diabetic cancer patients. In this review, the correlation between cancer and diabetes will be discussed and the mechanisms by which the two diseases interact with each other, as well as the therapeutics challenges in treating patients with diabetes and cancer with possible solutions to overcome these challenges. Natural products targeting both diseases were discussed with detailed mechanisms of action. This review will provide a solid base for researchers and physicians to test natural products as adjuvant alternative therapies to treat cancer in diabetic patients.

1. Introduction

Diabetes mellitus is a class of metabolic disorders characterized by prolonged periods of hyperglycemia. According to the World Health Organization (WHO), in the year 2014, 422 million people worldwide suffered from diabetes, and 1.6 million deaths were directly related to diabetes in the year 2016. Moreover, these statistics have been rising slowly over the last few decades 1. Diabetes mellitus (DM) is displayed as either type 1 diabetes mellitus (result from total insulin deficiency due to beta-cell death follow an autoimmune disease) or type 2 Diabetes Mellitus (predominantly resulting from insulin resistance, rendering target cells unable to effectively respond to insulin and so unable to utilize blood glucose for energy). It is well known that diabetes mellitus increases the risk of developing a variety of severe life-threatening health complications, resulting from the disruption and impairment in the function of several organs (kidneys, hearts, skin, blood vessels, or nerves), leading to both microvascular and macrovascular complications which include nephropathy, diabetic retinopathy, and neuropathy, as well as atherosclerosis, hypertension, and stroke. These diabetic vascular complications are responsible for the majority of mortality in diabetic patients 2. In addition to these complications, elevated blood glucose levels have been shown to stimulate cancer cell proliferation and progression 3. Studies have shown a strong correlation between diabetes mellitus and carcinogenesis and the most evident correlation is reported with type 2 diabetes mellitus (T2DM). Nevertheless, In type 1 diabetes mellitus (T1DM), the risk of carcinogenesis has also been identified but is less evident compared to that with T2DM 4. However, in both types of diabetes mellitus cancer incidence tends to be increased 5. Cancer is the second leading cause of death worldwide and in the year 2018, approximately 9.6 million deaths were attributed to cancer, and nearly one in six deaths around the world are caused by cancer 6. Both diabetes and cancer have a dramatic detrimental effect on both the mortality rate and the quality of life, and the simultaneous rise in incidence rates of both diseases has encouraged the research community to search into a possible correlation in terms of pathophysiological pathways and/or the common climate 7. Hyperglycemia causes epigenetic alterations by several mechanisms including DNA methylation and chromatin remodeling, resulting in abnormal gene expression. Moreover, in cancer, abnormal gene expression causes tumor growth by increasing the metastases, proliferation, and chemoresistance of cancer cells 8. The proliferation of cancer cells which is induced by hyperglycemia/diabetes occurs indirectly by mediating the following processes (1) insulin and insulin-like growth factor 1 (IGF-1), (2) secretion of leptin/adiponectin, (3) inflammatory responses, (4) production of reactive oxygen species (ROS; oxidative stress) and (5) immune abnormalities (platelet activation) 9. In addition to a direct correlation between impaired glucose tolerance/diabetes and the initiation of cancer, proliferation and invasiveness may occur due to hyperglycemia 10. Many epidemiological reports have shown that diabetes is positively associated with several types of cancers including breast, colorectal, endometrial, liver and pancreatic cancers. On the other hand, a decreased prevalence of prostate cancer has been observed in diabetic patients 11. Ben et al. found a significant association between DM and pancreatic with an inverse correlation between the duration of DM and the occurrence of pancreatic cancer in both sexes, thus observing the greatest risk of developing pancreatic cancer in patients with a duration of DM shorter than 1 year after diagnosis 12. Similar findings were observed in another study 13. Cancer risk in diabetic patients is 20% higher based on a meta-analysis of 20 studies 14. The analysis of data obtained by Hulda Hrund Bjornsdottir et al. on 450,000 people with type 2 diabetes and more than 2 million people without diabetes in Sweden between 1998 and 2014 was unable to show a cause-and-effect relationship. Nevertheless, people with blood sugar disease were observed to have a higher risk of developing several types of cancer including a 231% higher risk of hepatocellular cancer, a 119% higher risk of pancreatic cancer, and a 78% higher risk of uterine cancer compared to those without type 2 diabetes. Additionally, people with diabetes had an elevated risk of kidney cancer (45% higher), stomach cancer (21% higher), cancer of the gallbladder and bile duct (32% higher), and penile cancer (56% higher). Moreover, the incidence of colorectal cancer and bladder cancer was also 20% higher, while the breast cancer risk was 5% higher 15. Besides the increased risk of cancer by hyperglycemia/diabetes, several meta-analysis studies have also linked diabetes with a higher incidence of poor post-treatment prognosis in diabetic cancer subjects 16. In addition, the effect of hyperglycemia on breast cancer chemotherapy resistance have been shown in recent studies 17. Although epidemiological studies have shown that cancer mortality in diabetic patients is relatively increased, it is still unclear if this is a consequence of hyperglycemia and hyperinsulinemia (growth-promoting effect on cancer cells), poor health conditions attributable to diabetes comorbidity, or a combination of all these factors 18. There is strong evidence that cancer patients with diabetes are treated less aggressively or are expected to be less likely treated with modified anti-cancer therapy than non-diabetic cancer patients 19. Some anti-diabetic drugs, such as metformin, have been shown to reduce the incidence of cancer in diabetes patients, enhance the efficacy of anti-cancer drugs and also has shown favorable survival in cancer patients 16. This review presents a detailed discussion of the major metabolic changes in cancer cells that maintain their development. Furthermore, since diabetes is a metabolic syndrome we will discuss the metabolic linkage between diabetes and cancer. We also will describe therapeutic challenges facing treating diabetic patients with cancer and suggested therapies. Finally, we will explore various natural products that have the capacity to target both diseases and the mechanisms of action on both diseases.

2. Cancer Altered Metabolism

Generally, cancer cells have the ability to proliferate from one abnormal cell to more than 109 cells (the total number of cells ~1 cm in diameter in a tumor) if suitable conditions are available 20. Tumor cells will modify their metabolism to guarantee survival, overpower host immune attack, and maintain the proliferative capacity to induce their lethal effects and sustain survival 21. Cancer cells undergo physiological adaptations to preserve their survival under many stressful conditions, such as hypoxia and food hunger in order to fulfill their massive growth requirements. Such metabolic modifications generate abnormal metabolic events when compared to normal cells. This reprogrammed metabolism is seen as a cancer signature, as many metabolic modifications are predominant in several other types of cancers 22. Similar to normal cells, cancer cells also have to produce ATP to maintain both daughter cells formed through division, rely on metabolic intermediates or biosynthesis by-products and, most critically, to compete with the oxidizing effects to mitigate the impact of reactive oxygen species (ROS). These altered metabolic and bioenergetic mechanisms, significantly elevated biosynthesis and redox equilibrium, are crucial to cancer progression 23. Therefore, proliferating cells need to obtain high amounts of lipids, nucleotides, and amino acids. Through using by-products and derivatives of the TCA (tricarboxylic acid) cycle, cells can generate this biomass 24. It would appear that fulfilling all these requirements would require a significant boost in glucose uptake in tumors. The high glucose consumption in many, but not all, tumors have been verified by PET (positron emission tomography) imaging and glucose consumption rates beyond the levels that can be easily explained by energy or metabolite requirements 25. Moreover, the utilization of glutamine meets a symmetrical pattern of excessive consumption 26. It is believed that cancer metabolism could be described as upregulation of the metabolism of both glucose and glutamine for the production of energy.

2.1. Glucose

Glucose is the principal source of cellular energy and in the presence of oxygen, it is metabolized to pyruvate through glycolysis, which is transported to the mitochondria, where it is oxidatively metabolized into CO2 in the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation via electron transport chain (ETC) to produce high amounts of energy (for each molecule of glucose about 32 to 34 molecules of ATP are produced) 27. Cells may also undergo anaerobic glycolysis without oxygen, i.e., fermentation, diverting the resulting pyruvate molecules towards lactate production which is less effective in ATP production than the TCA cycle coupled with oxidative phosphorylation. Similarly, cancer cells primarily metabolize glucose, but in contrast to normal cells and in spite of the presence of oxygen, glycolysis produces lactate leading to the generation of two ATP per molecule of glucose. Consequently, cancer cells need a high glucose utilization efficiency so as to fulfill their energy and anabolic requirements, Otto Heinrich Warburg in 1920 found that even in ample oxygen, glycolysis was improved in cancer cells. However, glycolysis was commonly known to increase under anaerobic conditions 28. Despite deficiency in oxygen, increased glycolysis in cancer cells seemed to be a new phenomenon and was referred to as aerobic glycolysis or the “Warburg effect” 29. Consequently, the high quantity of glucose catabolism into lactate has been the most widespread metabolic phenotype detected in cancer cells, contributing to the deposition of lactate by-products within the tumor’s microenvironment 20. Currently, it is obvious that cancer cells experience aerobic glycolysis due to oncogene stimulation, tumor suppressor genes inhibition, and activation of phosphatidylinositol 3-kinase (PI3K) pathway, and that one benefit of high glycolytic frequencies is the availability of anabolic pathway substrates 30. The expression of glucose transporters in tumor cells is deregulated by some oncogenes (such as Myc oncogene), resulting in over-expression of these transporters, especially GLUT1 and GLUT3 31. The idea that cancer cells utilize glucose as a fuel is explained as follows; glucose begins to be processed in the cytosol, and is converted to glucose-6-phosphate (G6P) by Hexokinase (HK). Glucose-6-phosphate (G6P) is the splitting point from glycolysis to the pentose phosphate pathway oxidative branch (PPP) that produces the ribose group needed for nucleotide synthesis (RNA and DNA synthesis). This pathway is important in order to enable cancer cells to fulfill their anabolic demands and survive oxidative and nutritional stress 32. In this pathway, glucose-6-phosphate (G6P) is broken up into three-carbon compounds, 3-phosphoglyceraldehyde, which is the main point for the non-essential amino acid serine synthesis. Phosphoenolpyruvate (PEP) is also formed by glycolysis and end up producing two pyruvate molecules 20. The glycolytic enzyme pyruvate kinase enzyme (PK) is the final rate-limiting enzyme and is essential in pyruvate and ATP production. This enzyme has four isoforms (M1, M2, L, and R) which are expressed in different cell types. The PKM2 isoform is highly expressed in tumors thus shifting glucose metabolism towards anabolism through aerobic glycolysis and allowing the pyruvate product in the cytosol to be reduced to lactate by lactate dehydrogenase enzyme (LDH) 33,34,35. In cancer cells, lactate dehydrogenase enzyme (LDH) expression is upregulated which plays a crucial role in cancer characteristics 33.To sum up, cancer cells use catabolism of glucose as a main energy-generating mechanism by glycolysis and also from glucose, many biosynthetic compounds and NADPH molecules are produced.

2.2. Glutamine

The most common circulating amino acid in humans is glutamine. Glutamine is also the second most abundant nutrient after glucose in vitro cell culture environments, and its intake surpasses protein synthesis requirements 26. Via controlling mitochondrial reactive oxygen species (ROS) and proliferation, glutamine impacts the signaling pathways needed for cancer development, survival, and metabolism 36,37. Glutamine is taken up by proliferating cancer cells and converted to glutamate by various deamidation and transamination reactions, especially mitochondrial amidohydrolase glutaminase 38. Then, glutamate is transformed to alpha-ketoglutarate (α-KG) by glutamate dehydrogenase activity (or an aminotransferase) 39. Moreover, glutamine is used by rapidly developing tumor cells as a source of carbon for energy production as well as for the regenerating intermediates of the TCA cycle such as pyruvic acid, oxaloacetate, and α-KG to compensate for the continuous depletion of citrate exported from the mitochondria for lipid synthesis 37. (Figure 1) showing the metabolic alteration in cancer cell.

3. Diabetes Relationship with Metabolic Syndrome (MetS)

A metabolic syndrome was described for the first time by Reavan in 1988, in which he suggested that it was an essential feature in developing Chronic Heart disease (CHD) and Diabetes Mellitus type II (DMTII), mostly through insulin resistance 40. Afterwards, established criteria for metabolic syndrome clinical identification have been emerged by NCEP-ATP III (the National Cholesterol Education Program/Adult Treatment Panel III) 41,42, WHO (the World Health Organization), IDF (the International Diabetes Federation) 43, and AACE (the American Association Clinical Endocrinologists) 44 (Shown in Table 1).According to NHANES III (the 3rd National Health and Nutrition Examination Survey) criteria, almost 47 million people have metabolic syndrome 45. Moreover, more than 2 in 10 cancers in the UK are thought to be related to metabolic syndrome 46. The risk of developing metabolic syndrome is increased with age, and it has been estimated that, in the age group of over 50 years, more than 40% in the United States and nearly 30% in Europe of this age group have metabolic syndrome 47,48. Recently, Esposito et al. using a meta-analysis, examined 38,940 patients with metabolic syndrome and cancer, and the study results showed that metabolic syndrome increases the risk of several cancers including colorectal, pancreas, and liver cancers. However, the reported results showed differences between genders. In men, the metabolic syndrome was strongly linked with both liver and colorectal cancers but weakly linked with bladder cancer. On the other hand in women, the metabolic syndrome was linked with endometrial, pancreas, breast (especially in postmenopausal women), colorectal, and ovary cancers 49. Table 1 summarizes various definition of metabolic syndrome.Insulin is considered the primary anabolic hormone and has an essential function in stimulating cell proliferation 51. In healthy individuals, the blood glucose level is tightly controlled by both insulin release and insulin-mediated glucose uptake in the tissues 52. On the other hand, when the response of the normal cells to insulin is weakened, a condition called insulin resistance is produced. As a result, the pancreas β-cells respond to this condition by increasing the secretion of insulin into the circulation, causing hyperinsulinemia (High insulin concentration in the blood in order to maintain a normal blood glucose level 53. Insulin resistance creates a favorable environment for neoplastic tissue survival and cancer cell development 54,55,56, this could be explained through the abnormally elevated levels of growth factors, ROS (Reactive Oxygen Species), adipokines, and proinflammatory cytokines that are associated with this condition.The primary mechanism for many features of metabolic syndrome is suggested to be insulin resistance or hyperinsulinemia. Studies have shown that chronic hyperinsulinemia is also associated with several cancer types such as colorectal, pancreatic, endometrial, and breast cancers 57. Hyperinsulinemia reduces the production of IGFBP-I and -II (Insulin-like growth factor binding protein) thus increasing IGF-I (Insulin-like growth factor) level in the blood, and promoting tumor development by changing the cellular environment 58. In addition, hyperinsulinemia inhibits the synthesis of SHBG Sex hormone-binding Globulin leading to increased free sex hormone levels thus promoting sex hormone-dependent cancers such as endometrial, breast and prostate cancers 58. Metabolic syndrome is also characterized by hyperglycemia 29, however, this does not mean that every diabetic patient has MetS since it is about three times more common than diabetes 59. The results of a study done by Flood et al. to investigate the relationship between insulin, fasting glucose, and colorectal adenomas recurrence risk, showed that the risk for colorectal recurrence is higher in patients with elevated insulin and glucose 60.A relationship between insulin resistance or hyperinsulinemia with different types of epithelial cancers has been shown by several population-based studies. Initial studies on prostate cancers showed a link with plasma IGF-I concentration 61. On the other hand, different studies have confirmed that both elevated IGF-I and insulin levels are associated with prostate cancer risk, prospectively 62,63,64. Moreover, a link has been shown between hyperinsulinemia and breast cancer risk (measured by fasting C-peptide concentration) mainly in postmenopausal breast cancer 65 and also with endometrial cancer risk independent of estradiol 66.

4. Metabolic Link between Diabetes and Cancer

The potential metabolic links between DM and cancer development are hyperinsulinemia, hyperglycemia, and chronic inflammation due to fat imbalanced metabolism.

4.1. Hyperinsulinemia

The role of insulin’s in carcinogenesis is mainly influenced by insulin receptor (IR), Insulin-like Growth Factor (IGF), and Insulin-like Growth Factor Receptor (IGF-R) 4. In diverse human malignancies, it was found that there is overexpression in the IR, the fetal isoform IR-A in particular, and in the IGF-R 67,68. Moreover, tumor cells can produce hybrid forms of insulin and IGF-1 receptors that can either be activated by insulin, IGF-1, and/or IGF-2 69. Insulin receptor (IR) is composed of two α-subunits and two β-subunits, expresses the activity of tyrosine kinase and is strongly activated by insulin, while both IGF-1 and IGF-2 possess weaker activation 70,71. The biochemical processes of insulin signaling proceed via autophosphorylation of IR itself and its direct substrate followed by activation of several pathways including the lipid kinase phosphor-inositide-phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of the rapamycin signaling pathway (mTOR) eventually leading to carcinogenesis via abnormal cells proliferation and inhibition of apoptosis 72. Increased mitogenesis was also observed in activated IRs in an insulin-resistant environment 73. Due to the structural similarity between IGF-R and IR (approximately 60% homology), insulin may also activate IGF-R 73. Activation of IR produces mainly metabolic effects, on the contrary activation of IGF-R by insulin produces mitogenic effects including cell proliferation, angiogenesis, and metastasis 67,74. Studies have verified that restriction of calorie consumption leads to reduced levels of insulin and IGF-1, complemented by declined insulin resistance and repressed mTOR pathway 75,76. Furthermore, hyperinsulinemia stimulates an increase of IGF-1 level through hepatic activation of growth hormone receptor (GHR), resulting in increased secretion of growth hormone (GH) which stimulates IGF-1 77. An elevated level of IGF-1 is considered a predisposing factor for premenopausal breast, prostate and colorectal carcinogenesis 78. Additionally, hyperinsulinemia also leads to a decreased level of IGF-binding protein 1,2, and 3 resulting in an increased level of bioavailable IGF-1 67,79. Elevated insulin level also minimizes liver production of sex-hormone-binding-protein (SHBG) and shortage of this protein increases the level of bioavailable estrogen or testosterone thus increasing the risk of hormone-dependent cancers 80. Likewise, hyperinsulinemia enhances the production of leptin (the mitogenic adipokine) by hypoxia-inducible factor-1α (HIF-1α). Although the mitogenic effect of leptin was believed to stimulate proliferation of esophagus, breast, and prostate cancer cells; it showed inhibitory activity on pancreatic cancer cells 81.

4.2. Hyperglycemia

One of the notable characteristics of cancer cells is the increased uptake of glucose and enhanced glucose metabolism 82 to be able to grow and divide rapidly. Cancer cells possess altered metabolism via aerobic glycolysis, namely the “Warburg effect” 29. Hyperglycemia promotes tumor growth via proliferation, anti-apoptosis, and metastatic activity 83. The proliferative effect induced by hyperglycemia occurs as a result of overexpression of the following: glucose receptors (GLUT-1, GLUT-3) in tumor cells, protein kinase C (PKC-α), peroxisome proliferator-activated receptor (PPAR α and γ), and epithelial growth factor (EGF) 83. On the other hand, the anti-apoptotic activity of hyperglycemia is a consequence of the decreased level of prolyl hydroxylase (PDH) enzymes that eliminate the hypoxia-inducible factor α (HIF-α), thus leading to elevated HIF-α, which is a vital regulator of tumor cell survival in a hypoxic and anabolic environment. Additionally, hyperglycemia preserves cytochrome-c mediated apoptosis by elevated nicotinamide adenine dinucleotide phosphate (NADPH). Hyperglycemia also promotes metastasis and invasiveness due to several factors including epithelial to mesenchymal transition (ETM) process, oxidative stress via reduction of reactive oxygen species (ROS) and increased superoxide dismutase (SOD), and elevated expression of zinc transporters leading to enhanced zinc absorption which is involved in migration of cancer cells 84. Moreover, oxidative stress is a possible risk factor for carcinogenesis in diabetic people since it is the initial mechanism of insulin resistance; which is due to the inactivation of insulin receptors resulting from the overproduction of superoxide in the mitochondria 72.In addition, increased glucose levels affect the epigenetic regulation resulting in what is known as “hyperglycemic memory”; a condition that allows the activation of oncogenic pathways in hyperglycemia-exposed tumor cells, even after constant glucose level normalization 85. Glucose-induced constant expression of NF-κB p65-gene is the probable reason behind this mechanism 85. Interestingly Jee et al. suggested that fasting glucose level (FGL) > 125 mg/dL increases the risk of cancer incidence 86. On the contrary, a meta-analysis of major published trials clarified that the risk of cancer development was not reduced in type 2 diabetics who followed an intensified glycemic control 87.

4.3. Chronic Inflammation Due to Fat Imbalanced Metabolism

Obesity promotes tumorigenesis according to evolving studies 88,89 stressing that almost 80% of T2DM cases are associated with obesity and overweight 90. Numerous studies have also suggested that excess body adipose tissue is a risk factor for various types of cancers, including breast, endometrial, esophageal, pancreatic, and colorectal, cancers 88. The tumor-promoting activity of obesity can be probably explained by mechanisms such as alteration in sex hormones metabolism, changes in the levels of adipokines, chronic inflammation, and insulin resistance 80,88. Moreover, metabolic and mitogenic variations induced by excessive adipose tissue enhance the impact of hyperglycemia and hyperinsulinemia observed in T2DM. Figure 2 showed the metabolic relationship between diabetes and cancer.

4.4. Correlation between DM and Specific Cancer Examples

4.4.1. Liver Cancer

The most frequently observed malignant liver neoplasm in patients with DM is hepatocellular carcinoma (HCC) 91. The association between DM and a higher risk of HCC development was initially reported by Lawson in 1986 92, and was effectively supported by further researchers 91,93,94. These studies found that HCC is highly diagnosed in patients with non-alcoholic fatty liver disease (NAFLD), in obese patients with insulin resistance, and in T2DM patients 95,96. These disease conditions promote hepatic oncogenesis by several mechanisms, such as insulin resistance, modified adipokines pathophysiology, lipotoxicity and oxidative stress in the form of systemic inflammation. Furthermore, obesity accompanied by insulin resistance causes a decrease in adiponectin concentration and an increase in leptin, TNF-α, IL-6, and free fatty acids (FFA) concentrations, promoting growth, multiplication, and carcinogenesis in hepatic cells 96.Moreover, the liver is subjected to high insulin concentration as a result of portal circulation, thus leading to insulin-induced proliferation and suppression of apoptosis in hepatic cells 97.Additionally, HCC cells exhibit overexpression of both IGF-1 and insulin receptor substrate-1 (IRS-1), leading to the magnification of insulin effect. Furthermore, IRS-1 activates PI3K signaling and prevents apoptosis regulated by Transforming Growth Factor-β1 (TGF-β1), which is essential in hepatic cell carcinogenesis. Studies have also proposed that both T1DM and T2DM predispose to HCC, probably via hyperglycemia; in particular, a slightly stronger correlation was noted with T1DM than that with T2DM 98. On the other hand, data from various studies have suggested that T2DM with its simultaneous metabolic disorders activate oncogenesis in hepatic cells 99,100.

4.4.2. Prostate Cancer

Prostate cancer (PC) is the only described cancer in the literature associated with DM 101. Several studies reported the significant converse association between PC and DM which suggested a protective effect of DM against PC 101,102,103. Potential causes of this association involve a low testosterone level (probably due to high glucose level) and hypo-insulinemia observed in T1DM or T2DM in the long term. On the contrary, Li et al. suggested that DM is associated with an improved risk of advanced PC development 104.

5. Impact of Diabetes and Obesity on Cancer

Obesity is a major public health concern around the world, and it is now considered a crisis. It occurs as a result of changes in lifestyle (lack of physical activity, a high fat/calorie diet, a high carbohydrate diet) and is often related to lifestyle factors such as cigarette smoking and alcohol consumption. According to World Health Organization (WHO) over 1.9 billion people aged 18 and up were overweight in 2016. Over 650 million people were overweight (body mass index ≥ 25 kg/m2) or obese (body mass index ≥ 30 kg/m2) 105. Obesity and type 2 diabetes, “Diabesity is a new concept for diabetes that affects people who are obese” have become much more common across the world, which are commonly related to metabolic disorders and both are linked to a higher incidence and mortality rate which can accelerate cancer progression 106. Diabesity has been associated with the development of pancreatic cancer and its pathogenesis in many studies 107. In addition, it contributes to an increased risk of a number of different cancers, including breast, hematological and prostate cancer 108,109,110. Diabesity has been related to cancer progression through a number of mechanisms, including 1. insulin-like growth factor signaling, activation of the insulin/IGF signaling pathway has been presumed to lead to tumor initiation and/or progression just at the cellular level via tumor cell-specific mechanisms such as cell division activation and glucose metabolism 111 and epithelial-to-mesenchymal transition (EMT) 110 2. Insulin resistance and hyperinsulinemia are common in individuals with diabesity, C-peptide levels as indicators of insulin secretion have been tested in many studies to see whether hyperinsulinemia is related to cancer risk and mortality 112. A 37% increased risk of colorectal cancer has been linked to elevated C-peptide levels 113. According to the Physicians Health Report, obese men with increased C-peptide levels are likely to die from prostate cancer four times more than men with normal C-peptide levels 114. 3. Adipose tissue factors, adipose tissue is an important organ for the production of adipokines, inflammatory cytokines, and enzymes that are dysregulated in obesity and type 2 diabetes and potentially contribute to tumor growth and metastases 106,107,110. 4. Gut microbiome, Changes in the gut microbiota have been linked to an increased risk of some cancers by inducing inflammatory responses and leading to cancer proliferation 109. Recognizing the link between adipose tissue and tumors, the impact of obesity on immune cell function, and the effect of metabolic health on cancer progression will be crucial for enhancing current therapy responses and designing new therapies that address systemic metabolic.

6. Therapeutic Challenges in Treating Patients with Diabetes and Cancer

Various studies have indicated that cancer patients with diabetes have an inferior prognosis in comparison to non-diabetic patients. This could be explained since diabetes in cancer patients is a reason for higher infection rates, shorter remission periods, and higher mortality rates 55,115,116,117. Consequently, a variety of challenges face clinicians when treating cancer patients with diabetes because of the cardiac, neurologic, and renal complications associated with diabetic patients. Chemotherapeutic choices and treatment guidelines and, eventually, cancer outcomes could be affected due to the avoidance of using some of the best clinical agents with the best survival rates in cancer patients since these therapeutic agents may cause other disease complications 118.

6.1. Challenges Using Chemotherapeutic Agents

Cardiac, renal, and neuropathic complications usually develop in patients with poorly controlled diabetes and these complications can also be caused or exacerbated by many chemotherapeutic treatments. Anthracyclines, for example, may cause cardiotoxicity 119,120, and cisplatin could cause renal insufficiency. Consequently, the inability to use cisplatin in testicular cancer therapy decreases the overall response rates and survival 121. In addition, neurotoxicity, which is peripheral sensory neuropathy that occurs approximately in (40–50%) of diabetic patients, mainly in the feet, may also be caused by the use of cisplatin, vincristine, and paclitaxel; unfortunately, these side effects are usually permanent 122,123. Moreover, in order to achieve a successful cancer treatment, at least 85% of the chemotherapeutic dose should be given which necessitates careful monitoring of patients with cancer and diabetes before starting and during chemotherapy. Treatment of such patients must depend on the patient’s clinical picture since any alterations of the patient’s dose, time of administration, or changing between chemotherapeutic agents may affect the outcomes and lower the treatment response rate and also shorten patient’s survival rates 117,124,125.

6.2. Challenges Using Glucocorticoids

Several cancer treatment protocols regularly use glucocorticoids either in high doses for short-term therapy or in lower doses to alleviate nausea and vomiting that accompany treatment with chemotherapeutic agents. Therefore, before starting glucocorticoid therapy in any cancer patient, they should be tested for diabetes and also monitored closely after that, mostly because these patients have a high chance of being undiagnosed since up to a third of diabetic persons in the general public are undiagnosed 117. The mechanism of glucocorticoid action in raising blood glucose levels is by increased insulin resistance, glycogenolysis, gluconeogenesis, and decreased insulin production and secretion 126. Diagnosing cancer patients with diabetes during receiving glucocorticoid therapy is a common phenomenon as well. In addition, the most important factors for glucocorticoid-induced diabetes are increased age, obesity, a family history of diabetes or a history of gestational diabetes and treatment with high doses of steroids 127.

6.3. Challenges of Using Cancer Treatments While on Glucose-Lowering Treatments

Glucose-lowering treatments may influence cancer treatments and ultimately impact cancer-specific mortality. A retrospective study was carried out by MD Anderson Cancer Centre in order to determine whether treatment with metformin had affected the pathologic complete response (pCR) rates in females with both diabetes and breast cancer on treatment with neoadjuvant chemotherapy 128. The study showed that the rate of pCR was 24% for women on metformin treatment, 8.0% for women on therapy other than metformin, and 16% for non-diabetic women; those results highlight that many diabetic patients manifest a weakened response rate to chemotherapy in comparison with non-diabetic patients. Furthermore, another two recently published studies affirmed similar results when metformin was used by diabetic patients with colorectal cancer 129, and also patients with advanced non-small-cell lung cancer undergoing first-line chemotherapy 130.

7. Suggested Therapies for Cancer and Diabetes Patients

It is essential to state that glucose may be a potentially relevant cancer mediator taking into consideration the complexity of interactions between diabetes, diabetes treatments, and cancer. The Warburg hypothesis emphasizes how many types of cancer depend on glycolysis for energy, i.e., “glucose addiction” 29.One of the most effective diabetes management is to maintain improved control over blood glucose, thus reducing the risks of developing the complications associated with diabetes which leads to the minimization of morbidity and mortality rates. Therefore, regarding glucocorticoid therapy, rather than using a single bolus dose of steroids, giving steroids intravenous over 24 h or multiple doses during the day can better help control hyperglycemia in these patients. Diabetic patients treated with oral hypoglycemic medications may be kept on their medications while carefully monitoring their glucose levels. Nevertheless, in this case, these medications are usually inadequate for controlling hyperglycemia. On the other hand, diabetic patients who are on insulin therapy before starting the glucocorticoid therapy will usually need both basal and preprandial insulin administration and would need to increase their usual dose(s) of insulin two to three times. Moreover, in order to manage a patient’s induced or exacerbated hyperglycemia when using steroids, insulin is the preferred method in patients known with diabetes 126,127,131, and insulin doses are determined depending on the patient’s weight. A faster way to lower blood glucose levels is by intravenous insulin infusion which will also estimate the total required daily insulin dose for insulin naïve patients. However, many hospitals do not allow the use of intravenous insulin drips unless it is used in intensive care units due to the risk of hypoglycemia. Finally, insulin doses should be titrated daily and should also be tapered whenever glucocorticoid therapy is tapered in order to avoid hypoglycemia 126,127,131,132,133,134.In addition, clinicians often need a flexible approach to diabetes management in cancer patients because of the cyclical nature of chemotherapeutic agents, since platinum-based chemotherapy (e.g., cisplatin), mTOR kinase inhibitors (e.g., everolimus), and ABL kinase inhibitors (e.g., nilotinib) have all been connected to hyperglycemia.Unfortunately, there are few published articles related to this area. However, from the author’s experience, it is well known that diabetic patients with cancer need to be monitored frequently for hyperglycemic during therapy, especially in cases of advanced or incurable cancer patients undergoing palliative care 135.

8. Natural Products Targeting Diabetes and Cancer

8.1. Resveratrol

Resveratrol is a natural polyphenol that belongs to the class of stilbene 136. It is derived from various plant types and is presented in 34 families containing 100 species 137. In peanuts, soybeans, purple grapes and pomegranates, high resveratrol concentrations have been found 138. Resveratrol (3,5,40-trihydroxystilbene) is a stilbenoid and phytoalexin generated by a variety of plants as a result of injury or other pathogenic attacks 139. Resveratrol has historically been used to treat stomach pain, hepatitis, arthritis, urinary tract infections, and inflammatory and cardiovascular diseases 140. Several studies have recently reported the anticancer and antidiabetic effects of resveratrol.Resveratrol demonstrated antiproliferative and apoptotic effects on human cervical carcinoma cells by stimulating caspase-3 and caspase-9, impeding cell growth, inducing p53 expression, and upregulating the X-associated protein Bcl-2 141. It prevented the proliferation of colon cancer cells and induced cell apoptosis by suppressing the signaling pathway of AKT/STAT3 142. It enhanced paclitaxel’s apoptotic and oxidant effects by stimulating the TRPM2 channel in glioblastoma cells 143. Additionally, it inhibited pancreatic cancer cell metastasis by controlling the expressions of vimentin, CTA-2, IL-1β, TNF- α, and N-cadherin 144. Zhao et al. indicated that encapsulated resveratrol within peptide liposomes decreased free resveratrol’s toxicity and enhanced the physicochemical properties. It stimulated apoptosis in breast cancer by rising Bcl-2 activity, controlling p53 and Bax expression, and inducing the activation of caspase-3 145. A combination of thymoquinone and resveratrol was studied in both in vivo and in vitro models, and the findings demonstrated substantial cancer cell inhibition, angiogenesis suppression, and apoptosis elevation 146,147. A synergistic effect between resveratrol and doxorubicin against breast cancer cells was observed. In Ehrlich ascetic carcinoma cells carrying mice, combination therapy enhanced life span and decreased tumor volume 148.Resveratrol was examined in mice by analyzing postprandial glucose concentrations for its ability to inhibit α-glucosidase. The results showed that resveratrol delayed carbohydrate absorption, resulting in a reduced post-prandial blood glucose response 149. Several studies showed the antidiabetic effect of resveratrol 150. Resveratrol was revealed to enhance muscle and liver glucose absorption, decrease adipose tissue and liver inflammation, increase adaptive thermogenesis capability, and inhibit pancreatic insulin secretion 149. Quercetin and resveratrol were considered to have positive effects on diabetes. A study was conducted to investigate the combined antidiabetic action of quercetin and resveratrol in diabetic rats induced by streptozotocin. Elevated serum blood glucose, insulin levels, and dyslipidemia were significantly improved in diabetic rats by quercetin, resveratrol, and combination therapies. These compounds inhibited oxidative stress and tissue injury biomarkers substantially. Co-treatment of quercetin and resveratrol was useful against diabetes as it maintained the hepatic glucose metabolic enzymes activities and structure of pancreatic β-cells from the diabetes 151.

8.2. Curcumin

One of three components of phenolic difrauloylmethane compounds known as curcuminoids is curcumin. It is a major active ingredient found in Curcuma longa dried rhizomes (family: Zingiberaceae), generally referred to as turmeric 152,153,154. Curcumin has several pharmacological properties such as anticancer, anti-diabetic, antioxidant, antiviral, antibacterial, anti-inflammatory, and wound-healing ability 152,154,155,156,157. Curcumin has been recognized as an anticancer agent via various mechanisms of action, including cancer cell apoptosis activation, cancer cell metastasis suppression, and cancer cell growth inhibition 155,158,159,160. Curcumin has been identified in several signaling pathways such as activation of apoptotic ligand-inducing tumor-necrosis-factor-related apoptosis (TRAIL) pathways in HT-29 and HCT-116 colon cancer cells by upregulating death receptor factor 5 161. In HT-29 colon cancer, curcumin began Fas-mediated apoptotic pathway through caspase 8 activation 162. Bax expression was upregulated and Bcl-2 was inhibited via phosphorylation at Ser15 and p53 activation in HT-29 colon adenocarcinoma cells 163, and HCT-116 155. The anti-cancer effect of curcumin on osteosarcoma was reported by inhibition of MG-63 cell proliferation and migration and inactivation of JAK/STAT signal 164. Curcumin was also useful against prostate cancer as it interfered with nuclear factor κ (NFκB), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinase (MAPK) 165.A study revealed that 14 days treatment of human adipocytes with turmeric ethanol extract, containing curcumin, demethoxycurcumin, bisdemethoxycurcumin and ar-turmerone, led to improved adipocyte differentiation substantially in a dose-dependent manner, increase glucose elevation levels and enhance the activity of human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding 166. Furthermore, treatment of 3T3-L1 adipocytes with curcumin decreased glucose uptake, leptin levels, NF-kB p65 nuclear fraction, phospho-JNK1/2, phospho-IRS-1(S), MMP-2, MMP-9 and VEGF protein. However, it elevated insulin sensitivity, adiponectin levels, and IRS-2 protein 166.Curcumin supplementation greatly stopped the progression and disruption of the renal lesion. It decreased the levels of urinary enzymes (acid phosphatase, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)). Additionally, it decreased lactate dehydrogenase and renal glucose-6-phosphatase and increased ATPase activity 167. The co-administration of curcumin and metformin reduced JAK/STAT signalling pathway expression substantially to suppress myocardial degeneration and diminish lipid peroxidation levels, IL-6, creatine kinase-MB (CK-MB), troponin I, and tumor growth factor-β1 (TGF-β1) 168.

8.3. Thymoquinone

The major phytochemical bioactive constituent identified in volatile oil isolated from Nigella sativa (black cumin, black seed) is thymoquinone, which has been used in several countries as a traditional medicine 146,169,170. Thymoquinone has antihistaminic, immunomodulatory, antioxidant, antitumor, anti-inflammatory, and antimicrobial activities 170,171,172,173,174.Thymoquinone can be used as an anticancer agent as it can alter the regulation of cell cycle, growth factor, apoptosis, tumor-suppressor gene, protein kinase enzyme, transcription factors, survival signals, and phase I and II enzymes 170. Altering the progression of the cell cycle is an essential step in inhibiting the development and progression of cancer. Fatty acid-conjugated thymoquinone has a promising effect on apoptosis, cell proliferation, and signaling pathways 170. In the human mammary breast cancer epithelial cell line, MCF-7, thymoquinone induced cell arrest at various stages according to the concentration used (25 and 50 μM) in vivo 175. Furthermore, it was used to reduce serum TNF- α, IL-6, and iNOS enzyme production and improve histopathological outputs in Wistar rats with methotrexate-induced hepatorenal system injury 176. It played an important role in suppressing endothelial cell migration and tumor angiogenesis. In HCT 116 human colon cancer cells, thymoquinone significantly reduced the phosphorylation of EGFR to tyrosine-1173 residues and JAK2 in vitro 177. It has an antiproliferative effect, particularly when combined with doxorubicin and 5-fluorouracil, resulting in increased cytotoxicity in the xenograft mouse model of breast cancer 178. A study showed that thymoquinone activates apoptosis by reducing antiapoptotic protein expression 179.Thymoquinone has antidiabetic and antioxidant activities. It can reduce blood glucose level, triglycerides and cholesterol concentrations. On the other hand, it can improve the high-density lipoprotein, insulin sensitivity, and pancreatic β-cell regeneration resulting in substantial enhancement of the oral glucose tolerance test 180. Glycolysis and Kreb’s cycle pathways were used by thymoquinone to enhance glucose utilization while gluconeogenesis was used to decrease glucose production 181. Thymoquinone enhanced the antidiabetic effect of metformin 182. It can maintain the integrity of pancreatic β-cells by enhancing oxidative stress which subsequently raises the level of insulin 181. Nigella sativa consumption can reduce inflammatory and oxidative stress markers 183. Serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and malondialdehyde levels were significantly reduced by Nigella sativa intake, while total antioxidant ability and superoxide dismutase levels were significantly increased 183.

8.4. EGCG (Epigallocatechin Gallate)

The natural polyphenol that belongs to the class of flavonols is epigallocatechin-3-gallate (EGCG) 184. Green tea (Camellia sinensis, Theaceae) 185 and cocoa products 186 are the major dietary sources of EGCG. Green tea was utilized in the past as a diuretic, astringent, stimulant, and to improve heart health in Indian and Chines medicine 187. EGCG has numerous medical benefits, including suppression of tumor growth, inhibition of irregular blood clot formation, and reduction of LDL cholesterol levels 188. EGCG is the most effective anti-inflammatory and anticancer agent among the various green tea catechin derivatives 189.EGCG can be utilized as an anticancer agent as it has antimetastasis, antiproliferative, and pro-apoptosis activities. The antimetastasis activity of EGCG was mediated by suppression of MMP-2 protein expression through modulation of the Src signaling pathway 190. The synergistic chemotherapeutic potential was demonstrated by the combination of EGCG with eugenol or amarogentin in the cervical cancer cell line 191. The antiproliferative effect of EGCG was proved by its capability to suppress cyclinD1 and improve LIMD1, RBSP3, and p16 cell-cycle inhibitors at the G1/S cell cycle level 192. Moreover, by reducing multi-drug resistance 1 signaling and stimulating the AKT/STAT3 pathway, EGCG was capable to alert cisplatin-resistant oral cancer CAR cell apoptosis and autophagy 193. The effect of EGCG on doxorubicin-induced cytotoxicity of oral keratinocytes and anticancer activity against oral cancer cells was reported. It reduced the doxorubicin cytotoxic effect without impairing its anticancer efficacy 194.EGCG has an antidiabetic effect. In a reversible and non-competitive way, EGCG inhibited α-glucosidase because of the complex formation between EGCG and α-glucosidase, where the hydrogen bonds played an important role, EGCG quenched α-glucosidase fluorescence. EGCG strongly affected the secondary structure and the microenvironment of α-glucosidase. Furthermore, EGCG increased the glucose uptake and stimulated GLUT4 translocation to the plasma membrane through PI3K/AKT signaling pathway in L6 skeletal muscle cells 195.EGCG also has an antiobesity effect. Green tea supplementation can help obese patients lose weight and lower their body mass index by several mechanisms, including inhibition of ghrelin secretion and adipogenesis, improvement of adiponectin levels, and reduction of nutrient absorption 196.

8.5. Allicin

Allicin is a sulfenic acid thioester, or allyl thiosulfinate. It is predominantly present in garlic (Allium sativum) and belongs to the family Liliacerae 197. Allicin has various biological activities, including anticancer, antidiabetic, antimicrobial, and anti-inflammatory activity. Allicin substantially inhibited cholangiocarcinoma cell invasion and cell proliferation. It prohibited cell migration and prompted apoptosis via upregulation of SHP-1 and inhibition of the activation of STAT3 198. A study showed that allicin improved the X-ray radiotherapy sensitivity in colorectal cancer by inhibiting the signaling pathway of NF-κ 199. Furthermore, allicin demonstrated anti-tumor activity against HCMV-infected glioma cells through cytokine release downregulation, p53 activity stimulation, and radiotherapy sensitivity enhancement 200. Another study revealed allicin activity in stimulating apoptosis of cells and in suppressing ornithine decarboxylase which is a rate-limiting enzyme in neuroblastoma cell proliferation 201. By increasing cyclin D1 and reducing MMP-9 mRNA expression, allicin inhibited melanoma cell growth 202. Allicin also has synergistic anticancer activity against colorectal and lung carcinoma cells with 5-fluorouracil 203.Allicin has antidiabetic activities. It was helpful in the treatment of diabetic nephropathy 204. It enhanced insulin levels, reduced hyperglycemia, and prohibited changes in (GLUT4) and IRSs expression induced by diabetes 204. It also increased the expression of Nrf2 and decreased the expression of Keap1, HIF-1α, SBP, and VEGF 204. Treatment with allicin successfully decreased autoantibodies and anti-islet cell antibodies (ICA) for type 1 diabetes (IDDM). As a result, pancreatic tissues were restored and the decreased serum insulin level was greatly increased 205.

8.6. Emodin

Emodin is most widely isolated from the Rheum palmatum (Chinese rhubarb, family: Polygonaceae) roots and rhizomes. It is also existed in Polygonum multiflorum (Chinese knotweed), Polygonum cuspidatum (Asian knotweed), Cassia obtusifolia (Chinese senna, family: Fabaceae), Aloe vera (family: Asphodelaceae), Aspergillus wentii, and Aspergillus ochraceus 206,207,208,209. Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural derivative of anthraquinone 210. It has different Pharmacological activities, including antitumor, antimetastatic, antiproliferative, antidiabetic, antiviral, antibacterial, anti-inflammatory, and immunosuppressive activity 211,212,213,214. Emodin’s molecular mechanisms are apoptosis, cell cycle arrest, and expression promotion of the detoxification enzymes hypoxia-inducible factor 1α, glutathione phase I and II, and glutathione S-transferase P,N-acetyltransferase. Emodin can also inhibit angiogenesis, invasion, migration, and formation of chemical-induced carcinogen-DNA adducts, HER2/neu, CKII kinase, and p34cdc2 kinase human cancer cells 215. Tumor-associated angiogenesis was inhibited via the reduction of ERK phosphorylation.Emodin has an important role in the treatment of diabetic nephropathy. It can reduce hyperglycaemia and stimulate cell proliferation and fibronectin expression by preventing cellular FLICE-inhibitory protein (cFLIP) and p38MAPK pathway. Additionally, it has a PPARγ-activating effect. It improved the symptoms of diabetic animals through PPARγ pathway regulation. Furthermore, glycolysis was improved by emodin through the AMPK signalling pathway 216.

8.7. Genistein

Genistein 40,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one is an isoflavonoid derivative and it belongs to phytoestrogen classes. It exists in glycosylated or free forms in food (mainly legumes). It was firstly isolated from Genista tinctoria. It was also found in lycine max (Soybean), soy-based foods, soy-based drinks, Lupin (Lupinus perennis), broad beans and chick peas. Genistein has pharmacological activities, including anticancer, antidiabetic, antiosteoporetic, and estrogenic activity 217,218. The mechanisms of genistein as anticancer agent include reducing proliferation, preventing angiogenesis and metastasis, and stimulating apoptosis 219,220. Genistein has a good inhibitory effect against various cancer cell lines, including melanoma (MML-1 and SK-MEL-2), breast carcinoma (MDA-MB-231 and T47D), pancreas carcinoma (BxPC-3 and PANC-1), colon carcinoma (HT29 and COLO201), glioblastoma (U87 and LN229), and lung carcinoma (A549 and NCI-H460) 221. Genistein was documented to inhibit cyclooxygenase-2 (COX-2) directly and indirectly by suppressing COX-2-stimulating factors such as activated protein-1 (AP-1) and Nf-κB. In pancreatic, colon, breast, and lung cancers, COX-2 overexpression was recognized and its inhibition was associated with decreased cancerous tumor growth in the esophagus and colon 217.A study stated that genistein has anti-inflammatory and antidiabetic functions, especially direct effects on the proliferation of β-cells and the secretion of insulin. Genistein improved glucose homeostasis 222. In β-cells, phytonutrient genistein easily stimulated cAMP signaling. It also improved the mass of islets in diabetic mice. CAMP generation genistein stimulation was eliminated in islets exposed to G15 unique GPR30 inhibitor or GPR30 deficient islets (GPR30−/−) mice 223.

8.8. Parthenolide

In the Asterceae family of medicinal plants, especially in Tanacetum parthenium (feverfew) 224, parthenolide is an essential naturally occurring metabolite 225. It can also be found in Tanacetum vulgare (tansy) and Tanacetum larvatum 226. Parthenolide was traditionally utilized to treat rheumatoid arthritis, fever, and migraine, while lately, it has been shown to have anticancer effects in various types of cancer, including bladder cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, leukemia, prostate cancer, and cholangiocarcinoma 227. Parthenolide’s anticancer mechanisms include DNA replication inhibition 216, STAT3 inhibition, apoptotic pathway stimulation 217, p.53 activation, and upregulation the production of reactive oxygen species (ROS) 228. A study reported that parthenolide directly affected malignant cells without affecting normal cells 229. Parthenolide was effective against distinct cholangiocarcinoma cell lines 230, because it induced apoptosis. Parthenolide inhibited breast cancer stem-like cells by stimulating oxidative stress and necrosis 231. Furthermore, the growth of transplanted glioblastoma cells was significantly inhibited by parthenolide 232. In pancreatic cancer cells, parthenolide can improve gemcitabine’s antiproliferative effects 233.Parthenolide can reduce inflammation and remodel the impaired insulin signaling pathway, allowing cubilin and albumin uptake to be expressed 234. During adipogenesis, adipogenic factors and lipid accumulation were reduced by parthenolide. In a dose-dependent manner, parthenolide inhibited adipogenic factors (PPARc and C/EBPa) and its target protein FABP4 production 235. The regulation of reactive oxygen species production by parthenolide was linked to the control of the Nrf2-(Keap1) pathway 235.

8.9. Luteolin

Luteolin is a natural flavonoid abundantly present in many plant species. It is mainly found in vegetables and fruits, such as sweet bell peppers, carrots, onion leaves, broccoli, parsley, chrysanthemum flowers, and celery 236,237. It was isolated from Platycodon grandiflorum, Perilla frutescens, Apium graveolens, Cajanus cajan, Apium graveolens, Mentha spicata, and Sesbania grandifolra 238. Luteolin was utilized in the treatment of prostate, breast, pancreatic, skin, colon, oral, lung, ovarian, and kidney cancers 239. It has a potent cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and BT5-49 239. It obstructed cell proliferation and stimulated apoptosis of H460 and A549 cells 240,241,242. It inhibited metastasis, angiogenesis, and cell proliferation, and stimulated apoptosis through various mechanisms 243. The extrinsic and intrinsic apoptosis pathways were stimulated and the death receptor 5 expression was improved by luteolin 244. Stimulating JNK and obstructing translocation of NF-κB were mediated the cellular growth inhibition, G2 arrest, and apoptotic cell death induction 245. Furthermore, luteolin inhibited cancer cell proliferation by angiogenesis inhibition via blocking VEGF receptor stimulation and its downstream molecule PI3K/Akt and PI3K/p70S6 kinase pathways 246.Colon cancer and diabetes are the primary cause of death worldwide 247. Various luteolin signaling pathways, including SOD, p53, eNOS, Wnt, iNOS, MMP9, and the cyclin-CDK pathway, are used to treat cancer/diabetes 247. Since chronic hyperglycemia produces an intracellular level of reactive oxygen species, luteolin has anti-diabetic activity due to its antioxidant properties 247. Moreover, luteolin can regulate diabetes through mammalian targets of rapamycin (mTOR), cytokine, AMPK, and p53 247.

8.10. Quercetin

Quercetin is a polyphenolic flavonoid found in apples, berries, broccoli, onions, broccoli, green tea, red tea 248, Aesculus hippocastanum, Ginkgo biloba, and Hypericum perforatum 249. The biological activities of quercetin are anticancer, antidiabetic, antiobesity, neuroprotective, antimicrobial, antiviral, hepatoprotective, and anti-inflammatory activity 250. Quercetin stimulated apoptosis and inhibited cellular growth through the reduction of epidermal growth factor receptor (EGFR) expression 251. It induced apoptosis by directly upregulating caspase-3 and-9 and proapoptotic Bcl-2 family members, but it also induced apoptosis by directly downregulating antiapoptotic Bcl-xL 252. Moreover, it possessed a cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and MCF-7 via apoptosis activation along with G1 phase arrest 253,254. Quercetin improved the chemosensitivity of breast cancer cells to doxorubicin by obstructing proliferation and invasion of cells, leading to apoptosis activation 255. It also has good cytotoxic effects against human lung carcinoma A549 cells as it can inhibit cell invasion and migration, stimulate apoptosis, and decrease the number of tumor cells 256. A study showed that 16 weeks of administration of quercetin at a concentration of 200 and 400 mg/kg can decrease the number and the tumor size of papillomas in skin tumors prompted by croton oil in Swiss albino mice 257.Quercetin can decrease serum glucose level through several mechanisms, including antioxidant action, modulating hepatic gene expressions, obstructing α-glucosidase activity in vitro, and improving insulin action along with skeletal muscle mitochondrial biogenesis enhancement 258. It was utilized to reduce blood glucose and urine sugar levels, and increase plasma insulin and hemoglobin levels 259. Quercetin was found to be an effective PPAR-γ inhibitor 259.

8.11. Berberine

Berberine isolated from Coptis japonica Makino, Coptis chinensis Franch, and Berberis aristata Sims is an essential isoquinoline alkaloid. It is found in barberry, goldenseal, tree turmeric, and oregon grape 260. It is a pharmacologically significant secondary metabolite as it can help in the treatment of cancer, diabetes, and obesity 260.Colorectal, lung, liver, ovarian, prostate and cervical cancers are all inhibited by berberine 260. Under illumination with a black light lamp (320,450 nm; 20 W), SGC803 gastric cancer cells combined with berberine (10 g/mL) showed a good inhibitory proliferation effect. Additionally, berberine combined with 5-ALA-photodynamic therapy inhibits MGC-803 gastric cancer cell proliferation, reduces survivin and Bcl2 expression, stimulates cell apoptosis, and upregulates p53 and Bax expression. These findings imply that berberine has the ability to be utilized in conjunction with photosensitizers 260. Activating apoptosis and autophagy, inhibiting cell proliferation, and altering protein expression are berberine-photodynamic therapy’s mechanisms in treating tumors 260. Furthermore, berberine was utilized against breast cancer as it improved JNK phosphorylation, activated caspase-3, reduced the mitochondrial membrane potential, decreased the expression of Bcl-2, and increased the release of cytochrome c and AIF 261.Berberine decreased blood glucose and the risk of metabolic syndrome, improved insulin sensitivity, stimulated weight loss, improved lipid metabolism, reduced the levels of hemoglobin A1C and triglyceride, increased the mRNA expression of adiponectin, and reduced leptin and resistin secretion 262. Reduction of body weight, body mass index, and waist circumference was revealed after the administration of 500 mg of berberine either two or three times a day for three months 262.

8.12. Phytosterols

Phytosterols are plant-derived lipid compounds that are similar to cholesterol but differ in their carbon side chains and the presence or absence of a double bond. They are divided into two categories which are sterols (unsaturated compounds) and stanols (saturated molecules) 263. Phytosterols are commonly found in plants or macro fungi and have a number of pharmacological activities, including anticancer, hypolipidaemic, anti-inflammatory, and antidiabetic activity 263.Phytosterols can be utilized to improve breast, ovary, liver, lung, prostate and stomach cancers. They have several suggested mechanisms, including inhibition of carcinogen production, angiogenesis, cancer cell growth, multiplication, invasion, and metastasis and induction of apoptosis and cell cycle arrest 264. Female SCID mice were fed specified diets supplemented with 2% phytosterols, 2% cholesterol, or a 0.2% cholic acid vehicle to evaluate the effects of phytosterols on breast cancer cell growth and metastasis 264. After 2 weeks, mice were injected with MDA-MB-231 cells into their inguinal mammary fat pads. Eight weeks after the dietary supplementation, mice given phytosterols had a 40% reduction in serum cholesterol levels 264. Tumor sizes were 33% lower in animals fed the phytosterol diet compared to those fed the cholesterol diet 264. Tumor cell metastasis to lymph nodes and lungs was 57% of the phytosterol-fed animals and 71% of the cholesterol-fed animals 264. Another study showed that β-sitosterol enriched diet decreased tumor size in ovariectomized athymic mice injected with MCF-7 cells by 32–42% 264.Phytosterols have been shown to substantially lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the blood, and rise the HDL-C/LDL-C and HDL-C/TC indexes 265. Ergosterol could be a promising hypoglycemic agent for the treatment of type 2 diabetes, with a mechanism of stimulating GLUT4 translocation and expression through the PI3K/Akt and PKC pathways 265. Ergosterol was utilized to improve insulin resistance and blood lipid indices, and decrease fasting blood glucose levels. Furthermore, the phosphorylation of Akt and PKC was improved in different tissues 265. Table 2 summarizes the anticancer and antidiabetic mechanisms for selected natural products that target both diseases.

9. The Controversy of Exogenous Antioxidants Administration in Cancer

Research and studies about the role of reactive oxygen species (ROS) and the effect of exogenous administration of antioxidants’ supplements in cancer are opposed with controversy and conflicting outcomes. On one hand, antioxidants are commonly used by cancer patients and healthy individuals as a cancer-fighting strategy 269,270,271. Clinical trials with antioxidants, on the other hand, have shown contradictory findings; some trials showed that antioxidants raised cancer risks 272,273,274,275.Klein A et al. conducted a study between 2004 and 2011 and found that prostate cancer risk for healthy men was markedly increased upon supplementation with 400 IU/day of vitamin E supplement 276, whereas VI Sayin et al. clarified that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E noticeably enhances human lung cancer cells proliferation and tumor progression in mice with B-RAF- and K-RAS-induced lung cancer via decreasing ROS, DNA damage, and p53 levels. Additionally, Volkan S. et al. showed that the antioxidants supplementation may accelerate early tumors or precancerous lesions growth in elevated-risk populations (like smokers and chronic obstructive pulmonary disease patients who receive NAC to reduce mucus production) because the somatic p53 mutations occur late in the tumor progression process 277. Another study by Clotilde W. et al. demonstrated that long-term supplementation of NAC and vitamin E stimulates K-RAS-induced lung cancer metastasis by decreasing free heme levels and stabilizing the pro-metastatic basic leucine zipper transcription factor 1 (BACH1). BACH1 stimulates glycolysis-dependent metastasis of mouse and human lung cancer cells by activating transcription of Hexokinase 2 and Gapdh and increasing glucose uptake, glycolysis rates, and lactate secretion 278. Moreover, Le Gal et al. studied the effect of antioxidants on malignant melanoma in a mouse model and showed that the administration of NAC and Trolox (the soluble vitamin E analog) expand lymph node metastases and cause increased glutathione-synthesis-dependent invasiveness 279. Indicating that active tumors preserve ROS levels within limits that stimulate proliferation without leading to cytotoxicity 280. Similar results of melanoma metastasis were found in a different mouse model (NOD-SCID Il2rg−/− (NSG) mice) when supplemented regularly with subcutaneous injection of NAC 281. Clinical trials involving the use of antioxidants combined with chemotherapy are summarized in Table 3.In conclusion, the supplementation of exogenous antioxidants may aid cancer cells to navigate the metastatic cascade and adopt adaptive steps to counteract the beneficial effect of antioxidant supplements. Nevertheless; additional clinical studies are required to confirm the generalizability of these remarks and to expand them to practical application especially with existing cancer patients.

10. Conclusions

Cancer and diabetes represent global health challenges and the number of patients is contentiously increasing for both diseases. Hyperglycemia, hyperinsulinemia, and imbalanced fat metabolism in diabetic patients increase the altered metabolism in cancer cells. This metabolic link between cancer and diabetes complicates therapeutic protocols and reduces survival rates. Natural products with their diverse mechanisms of action can be used as adjuvant therapy to enhance conventional treatments. These natural products act by targeting interconnected mechanisms between cancer and diabetes. Further research is needed to explore the potential use of natural products in combination therapies to treat cancer in diabetic patients.

Funding

The authors are grateful to the Applied Science Private University, Amman, Jordan, for the full financial support granted to this research (Grant No. DRGS-2020-2021-4).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

159. Zimmet, P.; Alberti, K.G.; Magliano, D.J.; Bennett, P.H. Diabetes mellitus statistics on prevalence and mortality: Facts and fallacies. Nat. Rev. Endocrinol.2016, 12, 616–622. Google Scholar CrossRef
160. Asmat, U.; Abad, K.; Ismail, K. Diabetes mellitus and oxidative stress—A concise review. Saudi Pharm. J.2016, 24, 547–553. Google Scholar CrossRef Green Version
161. Giri, B.; Dey, S.; Das, T.; Sarkar, M.; Banerjee, J.; Dash, S.K. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed. Pharmacother.2018, 107, 306–328. Google Scholar CrossRef
162. Wojciechowska, J.; Krajewski, W.; Bolanowski, M.; Kręcicki, T.; Zatoński, T. Diabetes and cancer: A review of current knowledge. Exp. Clin. Endocrinol. Diabetes2016, 124, 263–275. Google Scholar CrossRef
163. Suh, S.; Kim, K.-W. Diabetes and cancer: Cancer should be screened in routine diabetes assessment. Diabetes Metab. J.2019, 43, 733. Google Scholar CrossRef
164. De Martel, C.; Georges, D.; Bray, F.; Ferlay, J.; Clifford, G.M. Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis. Lancet Glob. Health2020, 8, e180–e190. Google Scholar CrossRef Green Version
165. Cignarelli, A.; Genchi, V.A.; Caruso, I.; Natalicchio, A.; Perrini, S.; Laviola, L.; Giorgino, F. Diabetes and cancer: Pathophysiological fundamentals of a ‘dangerous affair’. Diabetes Res. Clin. Pract.2018, 143, 378–388. Google Scholar CrossRef
166. Lee, C.; An, D.; Park, J. Hyperglycemic memory in metabolism and cancer. Horm. Mol. Biol. Clin. Investig.2016, 26, 77–85. Google Scholar CrossRef
167. Ferroni, P.; Riondino, S.; Buonomo, O.; Palmirotta, R.; Guadagni, F.; Roselli, M. Type 2 diabetes and breast cancer: The interplay between impaired glucose metabolism and oxidant stress. Oxid. Med. Cell. Longev.2015, 2015, 183928. Google Scholar CrossRef
168. Srivastava, S.P.; Goodwin, J.E. Cancer biology and prevention in diabetes. Cells2020, 9, 1380. Google Scholar CrossRef
169. Sampayo, V.; Tofthagen, C. Hyperglycemia and Cancer: An algorithm to guide oncology nurses. Clin. J. Oncol. Nurs.2017, 21, 345–352. Google Scholar CrossRef
170. Ben, Q.; Xu, M.; Ning, X.; Liu, J.; Hong, S.; Huang, W.; Zhang, H.; Li, Z. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur. J. Cancer2011, 47, 1928–1937. Google Scholar CrossRef
171. Elena, J.W.; Steplowski, E.; Yu, K.; Hartge, P.; Tobias, G.S.; Brotzman, M.J.; Chanock, S.J.; Stolzenberg-Solomon, R.Z.; Arslan, A.A.; Bueno-de-Mesquita, H.B. Diabetes and risk of pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control2013, 24, 13–25. Google Scholar CrossRef
172. Villarreal-Garza, C.; Shaw-Dulin, R.; Lara-Medina, F.; Bacon, L.; Rivera, D.; Urzua, L.; Aguila, C.; Ramirez-Morales, R.; Santamaria, J.; Bargallo, E. Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. Exp. Diabetes Res.2012, 2012, 732027. Google Scholar CrossRef
173. Bjornsdottir, H.H.; Rawshani, A.; Rawshani, A.; Franzén, S.; Svensson, A.-M.; Sattar, N.; Gudbjörnsdottir, S. A national observation study of cancer incidence and mortality risks in type 2 diabetes compared to the background population over time. Sci. Rep.2020, 10, 1–12. Google Scholar CrossRef
174. Samuel, S.M.; Varghese, E.; Varghese, S.; Büsselberg, D. Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat. Rev.2018, 70, 98–111. Google Scholar CrossRef Green Version
175. Zeng, L.; Zielinska, H.; Arshad, A.; Shield, J.; Bahl, A.; Holly, J.; Perks, C. Hyperglycaemia-induced chemoresistance in breast cancer cells: Role of the estrogen receptor. Endocr. Relat. Cancer2016, 23, 125–134. Google Scholar CrossRef PubMed Green Version
176. Vigneri, P.; Frasca, F.; Sciacca, L.; Pandini, G.; Vigneri, R. Diabetes and cancer. Endocr. Relat. Cancer2009, 16, 1103–1123. Google Scholar CrossRef PubMed Green Version
177. Harding, J.L.; Andes, L.J.; Gregg, E.W.; Cheng, Y.J.; Weir, H.K.; Bullard, K.M.; Burrows, N.R.; Imperatore, G. Trends in cancer mortality among people with vs. without diabetes in the USA, 1988–2015. Diabetologia2020, 63, 75–84. Google Scholar CrossRef PubMed
178. Lunt, S.Y.; Vander Heiden, M.G. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol.2011, 27, 441–464. Google Scholar CrossRef Green Version
179. Villalba, M.; Rathore, M.G.; Lopez-Royuela, N.; Krzywinska, E.; Garaude, J.; Allende-Vega, N. From tumor cell metabolism to tumor immune escape. Int. J. Biochem. Cell Biol.2013, 45, 106–113. Google Scholar CrossRef Green Version
180. Pavlova, N.N.; Thompson, C.B. The emerging hallmarks of cancer metabolism. Cell Metab.2016, 23, 27–47. Google Scholar CrossRef Green Version
181. DeBerardinis, R.J.; Chandel, N.S. Fundamentals of cancer metabolism. Sci. Adv.2016, 2, e1600200. Google Scholar CrossRef Green Version
182. Danhier, P.; Bański, P.; Payen, V.L.; Grasso, D.; Ippolito, L.; Sonveaux, P.; Porporato, P.E. Cancer metabolism in space and time: Beyond the Warburg effect. Biochim. Biophys. Acta (BBA) Bioenerg.2017, 1858, 556–572. Google Scholar CrossRef
183. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell2011, 144, 646–674. Google Scholar CrossRef Green Version
184. Matés, J.M.; Campos-Sandoval, J.A.; de Los Santos-Jiménez, J.; Márquez, J. Dysregulation of glutaminase and glutamine synthetase in cancer. Cancer Lett.2019, 467, 29–39. Google Scholar CrossRef
185. Bose, S.; Le, A. Glucose Metabolism in Cancer. Adv. Exp. Med. Biol.2018, 1063, 3–12. Google Scholar PubMed
186. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol.1927, 8, 519–530. Google Scholar CrossRef PubMed Green Version
187. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science2009, 324, 1029–1033. Google Scholar CrossRef PubMed Green Version
188. Patra, K.C.; Wang, Q.; Bhaskar, P.T.; Miller, L.; Wang, Z.; Wheaton, W.; Chandel, N.; Laakso, M.; Muller, W.J.; Allen, E.L. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell2013, 24, 213–228. Google Scholar CrossRef PubMed Green Version
189. Hsieh, A.L.; Walton, Z.E.; Altman, B.J.; Stine, Z.E.; Dang, C.V. Seminars in Cell & Developmental Biology. In MYC and Metabolism on the Path to Cancer; Elsevier: Amsterdam, The Netherlands, 2015; pp. 11–21. Google Scholar
190. Fadaka, A.; Ajiboye, B.; Ojo, O.; Adewale, O.; Olayide, I.; Emuowhochere, R. Biology of glucose metabolization in cancer cells. J. Oncol. Sci.2017, 3, 45–51. Google Scholar CrossRef
191. Feng, Y.; Xiong, Y.; Qiao, T.; Li, X.; Jia, L.; Han, Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med.2018, 7, 6124–6136. Google Scholar CrossRef Green Version
192. Palsson-McDermott, E.M.; Curtis, A.M.; Goel, G.; Lauterbach, M.A.; Sheedy, F.J.; Gleeson, L.E.; van den Bosch, M.W.; Quinn, S.R.; Domingo-Fernandez, R.; Johnston, D.G. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab.2015, 21, 65–80. Google Scholar CrossRef Green Version
193. Seton-Rogers, S. Feed it forward. Nat. Rev. Cancer2011, 11, 461. Google Scholar CrossRef
194. Daye, D.; Wellen, K.E. Seminars in Cell & Developmental Biology. In Metabolic Reprogramming in Cancer: Unraveling the Role of Glutamine in Tumorigenesis; Elsevier: Amsterdam, The Netherlands, 2012; pp. 362–369. Google Scholar
195. Phan, L.M.; Yeung, S.-C.J.; Lee, M.-H. Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol. Med.2014, 11, 1. Google Scholar PubMed
196. Hensley, C.T.; Wasti, A.T.; DeBerardinis, R.J. Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J. Clin. Investig.2013, 123, 3678–3684. Google Scholar CrossRef Green Version
197. Deshmukh, A.; Deshpande, K.; Arfuso, F.; Newsholme, P.; Dharmarajan, A. Cancer stem cell metabolism: A potential target for cancer therapy. Mol. Cancer2016, 15, 1–10. Google Scholar CrossRef Green Version
198. Reaven, G.M. Role of insulin resistance in human disease. Diabetes1988, 37, 1595–1607. Google Scholar CrossRef PubMed
199. Alberti, K.; Eckel, R.H.; Grundy, S.M.; Zimmet, P.Z.; Cleeman, J.I.; Donato, K.A.; Fruchart, J.-C.; James, W.P.T.; Loria, C.M.; Smith, S.C., Jr. Harmonizing the metabolic syndrome: A joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation2009, 120, 1640–1645. Google Scholar
200. Lakka, H.-M.; Laaksonen, D.E.; Lakka, T.A.; Niskanen, L.K.; Kumpusalo, E.; Tuomilehto, J.; Salonen, J.T. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA2002, 288, 2709–2716. Google Scholar CrossRef
201. Alberti, K.G.M.M.; Zimmet, P.; Shaw, J. Metabolic syndrome—A new world-wide definition. A consensus statement from the international diabetes federation. Diabet. Med.2006, 23, 469–480. Google Scholar CrossRef
202. Ford, E.S. Insulin resistance syndrome: The public health challenge. Endocr. Pract.2003, 9, 23. Google Scholar CrossRef
203. Ford, E.S.; Giles, W.H.; Dietz, W.H. Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA2002, 287, 356–359. Google Scholar CrossRef PubMed
204. Nashar, K.; Egan, B.M. Relationship between chronic kidney disease and metabolic syndrome: Current perspectives. Diabetes Metab. Syndr. Obes. Targets Ther.2014, 7, 421. Google Scholar CrossRef Green Version
205. Cameron, A.J.; Shaw, J.E.; Zimmet, P.Z. The metabolic syndrome: Prevalence in worldwide populations. Endocrinol. Metab. Clin.2004, 33, 351–375. Google Scholar CrossRef
206. Ford, E.S.; Giles, W.H.; Mokdad, A.H. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care2004, 27, 2444–2449. Google Scholar CrossRef Green Version
207. Esposito, K.; Chiodini, P.; Colao, A.; Lenzi, A.; Giugliano, D. Metabolic syndrome and risk of cancer: A systematic review and meta-analysis. Diabetes Care2012, 35, 2402–2411. Google Scholar CrossRef Green Version
208. Alberti, K.G.M.; Zimmet, P.; Shaw, J. The metabolic syndrome—A new worldwide definition. Lancet2005, 366, 1059–1062. Google Scholar CrossRef
209. Duvnjak, L.; Duvnjak, M. The metabolic syndrome-an ongoing story. J. Physiol. Pharmacol.2009, 60 (Suppl. S7), 19–24. Google Scholar
210. Djiogue, S.; Nwabo Kamdje, A.H.; Vecchio, L.; Kipanyula, M.J.; Farahna, M.; Aldebasi, Y.; Seke Etet, P. Insulin resistance and cancer: The role of insulin and IGFs. Endocr. Relat. Cancer2013, 20, R1–R17. Google Scholar CrossRef Green Version
211. Cowey, S.; Hardy, R.W. The metabolic syndrome: A high-risk state for cancer? Am. J. Pathol.2006, 169, 1505–1522. Google Scholar CrossRef PubMed
212. Etet, P.F.S.; Vecchio, L.; Kamdje, A.H.N. Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: Any role for Notch, Wnt and Hh signaling pathways? Cell. Signal.2012, 24, 1433–1443. Google Scholar CrossRef
213. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat. Rev. Cancer2012, 12, 159–169. Google Scholar CrossRef
214. Sakurai, T.; Kudo, M. Signaling pathways governing tumor angiogenesis. Oncology2011, 81 (Suppl. S1), 24–29. Google Scholar CrossRef
215. Jee, S.H.; Kim, H.J.; Lee, J. Obesity, insulin resistance and cancer risk. Yonsei Med. J.2005, 46, 449. Google Scholar CrossRef Green Version
216. Calle, E.E.; Kaaks, R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer2004, 4, 579–591. Google Scholar CrossRef
217. Saklayen, M.G. The Global Epidemic of the Metabolic Syndrome. Curr. Hypertens. Rep.2018, 20, 12. Google Scholar CrossRef PubMed Green Version
218. Flood, A.; Mai, V.; Pfeiffer, R.; Kahle, L.; Remaley, A.T.; Lanza, E.; Schatzkin, A. Elevated serum concentrations of insulin and glucose increase risk of recurrent colorectal adenomas. Gastroenterology2007, 133, 1423–1429. Google Scholar CrossRef PubMed
219. Chan, J.M.; Stampfer, M.J.; Giovannucci, E.; Gann, P.H.; Ma, J.; Wilkinson, P.; Hennekens, C.H.; Pollak, M. Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study. Science1998, 279, 563–566. Google Scholar CrossRef
220. Giovannucci, E.; Rimm, E.B.; Liu, Y.; Willett, W.C. Height, predictors of C-peptide and cancer risk in men. Int. J. Epidemiol.2004, 33, 217–225. Google Scholar CrossRef
221. Harman, S.M.; Metter, E.J.; Blackman, M.R.; Landis, P.K.; Carter, H.B. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer. J. Clin. Endocrinol. Metab.2000, 85, 4258–4265. Google Scholar CrossRef
222. Kaaks, R.; Lukanova, A.; Rinaldi, S.; Biessy, C.; Söderberg, S.; Olsson, T.; Stenman, U.-H.; Riboli, E.; Hallmans, G.; Stattin, P. Interrelationships between plasma testosterone, SHBG, IGF-I, insulin and leptin in prostate cancer cases and controls. Eur. J. Cancer Prev.2003, 12, 309–315. Google Scholar CrossRef
223. Verheus, M.; Peeters, P.H.; Rinaldi, S.; Dossus, L.; Biessy, C.; Olsen, A.; Tjønneland, A.; Overvad, K.; Jeppesen, M.; Clavel-Chapelon, F. Serum C-peptide levels and breast cancer risk: Results from the European prospective investigation into cancer and nutrition (EPIC). Int. J. Cancer2006, 119, 659–667. Google Scholar CrossRef Green Version
224. Gunter, M.J.; Hoover, D.R.; Yu, H.; Wassertheil-Smoller, S.; Manson, J.E.; Li, J.; Harris, T.G.; Rohan, T.E.; Xue, X.; Ho, G.Y. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol. Prev. Biomark.2008, 17, 921–929. Google Scholar CrossRef Green Version
225. Kourelis, T.V.; Siegel, R.D. Metformin and cancer: New applications for an old drug. Med. Oncol.2012, 29, 1314–1327. Google Scholar CrossRef
226. Uzunlulu, M.; Caklili, O.T.; Oguz, A. Association between metabolic syndrome and cancer. Ann. Nutr. Metab.2016, 68, 173–179. Google Scholar CrossRef
227. Belfiore, A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr. Pharm. Des.2007, 13, 671–686. Google Scholar CrossRef PubMed
228. Kiselyov, V.V.; Versteyhe, S.; Gauguin, L.; De Meyts, P. Harmonic oscillator model of the insulin and IGF1 receptors’ allosteric binding and activation. Mol. Syst. Biol.2009, 5, 243. Google Scholar CrossRef PubMed
229. Scapin, G.; Dandey, V.P.; Zhang, Z.; Prosise, W.; Hruza, A.; Kelly, T.; Mayhood, T.; Strickland, C.; Potter, C.S.; Carragher, B. Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis. Nature2018, 556, 122–125. Google Scholar CrossRef PubMed
230. Cui, Y.; Andersen, D.K. Diabetes and pancreatic cancer. Endocr. Relat. Cancer2012, 19, F9–F26. Google Scholar CrossRef PubMed
231. Del Barco, S.; Vazquez-Martin, A.; Cufí, S.; Oliveras-Ferraros, C.; Bosch-Barrera, J.; Joven, J.; Martin-Castillo, B.; Menendez, J.A. Metformin: Multi-faceted protection against cancer. Oncotarget2011, 2, 896. Google Scholar CrossRef PubMed Green Version
232. Noto, H.; Goto, A.; Tsujimoto, T.; Osame, K.; Noda, M. Latest insights into the risk of cancer in diabetes. J. Diabetes Investig.2013, 4, 225–232. Google Scholar CrossRef Green Version
233. Anisimov, V.N. Metformin for aging and cancer prevention. Aging2010, 2, 760. Google Scholar CrossRef Green Version
234. Memmott, R.M.; Dennis, P.A. LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J. Clin. Oncol.2009, 27, e226. Google Scholar CrossRef
235. Baxter, R.; Brown, A.; Turtle, J. Association between serum insulin, serum somatomedin and liver receptors for human growth hormone in streptozotocin diabetes. Horm. Metab. Res.1980, 12, 377–381. Google Scholar CrossRef
236. Gallagher, E.J.; LeRoith, D. Diabetes, cancer, and metformin: Connections of metabolism and cell proliferation. Ann. N. Y. Acad. Sci.2011, 1243, 54–68. Google Scholar CrossRef
237. Friberg, E.; Mantzoros, C.S.; Wolk, A. Diabetes and risk of endometrial cancer: A population-based prospective cohort study. Cancer Epidemiol. Prev. Biomark.2007, 16, 276–280. Google Scholar CrossRef Green Version
238. Van Kruijsdijk, R.C.; Van Der Wall, E.; Visseren, F.L. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol. Prev. Biomark.2009, 18, 2569–2578. Google Scholar CrossRef Green Version
239. Somasundar, P.; Alice, K.Y.; Vona-Davis, L.; McFadden, D.W. Differential effects of leptin on cancer in vitro. J. Surg. Res.2003, 113, 50–55. Google Scholar CrossRef
240. Adekola, K.; Rosen, S.T.; Shanmugam, M. Glucose transporters in cancer metabolism. Curr. Opin. Oncol.2012, 24, 650. Google Scholar CrossRef
241. Ryu, T.Y.; Park, J.; Scherer, P.E. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab. J.2014, 38, 330. Google Scholar CrossRef Green Version
242. Fukada, T.; Yamasaki, S.; Nishida, K.; Murakami, M.; Hirano, T. Zinc homeostasis and signaling in health and diseases. JBIC J. Biol. Inorg. Chem.2011, 16, 1123–1134. Google Scholar CrossRef PubMed Green Version
243. Siebel, A.L.; Fernandez, A.Z.; El-Osta, A. Glycemic memory associated epigenetic changes. Biochem. Pharmacol.2010, 80, 1853–1859. Google Scholar CrossRef PubMed
244. Jee, S.H.; Ohrr, H.; Sull, J.W.; Yun, J.E.; Ji, M.; Samet, J.M. Fasting serum glucose level and cancer risk in Korean men and women. JAMA2005, 293, 194–202. Google Scholar CrossRef Green Version
245. Johnson, J.; Bowker, S. Intensive Glycaemic Control and Cancer Risk in Type 2 Diabetes: A Meta-Analysis of Major Trials; Springer: Berlin/Heidelberg, Germany, 2011. Google Scholar
246. Renehan, A.G.; Zwahlen, M.; Egger, M. Adiposity and cancer risk: New mechanistic insights from epidemiology. Nat. Rev. Cancer2015, 15, 484–498. Google Scholar CrossRef PubMed
247. Shu, X.; Hildebrandt, M.; Gu, J.; Tannir, N.; Matin, S.; Karam, J.; Wood, C.; Wu, X. MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity. Br. J. Cancer2017, 116, 77–84. Google Scholar CrossRef Green Version
248. Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and Cancer: A Consensus Report. CA Cancer J. Clin.2010, 60, 207–221. Google Scholar CrossRef Green Version
249. Davila, J.; Morgan, R.; Shaib, Y.; McGlynn, K.; El-Serag, H. Diabetes increases the risk of hepatocellular carcinoma in the United States: A population based case control study. Gut2005, 54, 533–539. Google Scholar CrossRef
250. Lawson, D.; Gray, J.; McKillop, C.; Clarke, J.; Lee, F.; Patrick, R. Diabetes mellitus and primary hepatocellular carcinoma. Qjm Int. J. Med.1986, 61, 945–955. Google Scholar
251. Dyson, J.; Jaques, B.; Chattopadyhay, D.; Lochan, R.; Graham, J.; Das, D.; Aslam, T.; Patanwala, I.; Gaggar, S.; Cole, M. Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol.2014, 60, 110–117. Google Scholar CrossRef
252. Wang, C.; Wang, X.; Gong, G.; Ben, Q.; Qiu, W.; Chen, Y.; Li, G.; Wang, L. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: A systematic review and meta-analysis of cohort studies. Int. J. Cancer2012, 130, 1639–1648. Google Scholar CrossRef
253. Kampf, G. Efficacy of ethanol against viruses in hand disinfection. J. Hosp. Infect.2018, 98, 331–338. Google Scholar CrossRef
254. Noureddin, M.; Rinella, M.E. Nonalcoholic Fatty Liver Disease, Diabetes, Obesity, and Hepatocellular Carcinoma. Clin. Liver Dis.2015, 19, 361–379. Google Scholar CrossRef
255. Wiencke, J.K. Impact of race/ethnicity on molecular pathways in human cancer. Nat. Rev. Cancer2004, 4, 79–84. Google Scholar CrossRef
256. Wang, P.; Kang, D.; Cao, W.; Wang, Y.; Liu, Z. Diabetes mellitus and risk of hepatocellular carcinoma: A systematic review and meta-analysis. Diabetes/Metab. Res. Rev.2012, 28, 109–122. Google Scholar CrossRef
257. Qiao, G.; Le, Y.; Li, J.; Wang, L.; Shen, F. Glycogen Synthase Kinase-3β Is Associated with the Prognosis of Hepatocellular Carcinoma and May Mediate the Influence of Type 2 Diabetes Mellitus on Hepatocellular Carcinoma. PLoS ONE2014, 9, e105624. Google Scholar CrossRef
258. Tan, Y.; Wei, S.; Zhang, W.; Yang, J.; Yang, J.; Yan, L. Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: A meta-analysis and systematic review. Cancer Manag. Res.2019, 11, 705–713. Google Scholar CrossRef Green Version
259. Kasper, J.S.; Giovannucci, E. A Meta-analysis of Diabetes Mellitus and the Risk of Prostate Cancer. Cancer Epidemiol. Biomark. Prev.2006, 15, 2056. Google Scholar CrossRef PubMed Green Version
260. Bansal, D.; Bhansali, A.; Kapil, G.; Undela, K.; Tiwari, P. Type 2 diabetes and risk of prostate cancer: A meta-analysis of observational studies. Prostate Cancer Prostatic Dis.2013, 16, 151–158. Google Scholar CrossRef PubMed
261. Waters, K.M.; Henderson, B.E.; Stram, D.O.; Wan, P.; Kolonel, L.N.; Haiman, C.A. Association of Diabetes With Prostate Cancer Risk in the Multiethnic Cohort. Am. J. Epidemiol.2009, 169, 937–945. Google Scholar CrossRef PubMed Green Version
262. Li, Q.; Kuriyama, S.; Kakizaki, M.; Yan, H.; Sone, T.; Nagai, M.; Sugawara, Y.; Ohmori-Matsuda, K.; Hozawa, A.; Nishino, Y.; et al. History of diabetes mellitus and the risk of prostate cancer: The Ohsaki Cohort Study. Cancer Causes Control2010, 21, 1025–1032. Google Scholar CrossRef PubMed
263. Ataey, A.; Jafarvand, E.; Adham, D.; Moradi-Asl, E. The relationship between obesity, overweight, and the human development index in world health organization eastern mediterranean region countries. J. Prev. Med. Public Health2020, 53, 98. Google Scholar CrossRef PubMed
264. Cohen, D.H.; LeRoith, D. Obesity, type 2 diabetes, and cancer: The insulin and IGF connection. Endocr. Relat. Cancer2012, 19, F27–F45. Google Scholar CrossRef
265. Gallagher, E.J.; LeRoith, D. Obesity and diabetes: The increased risk of cancer and cancer-related mortality. Physiol. Rev.2015, 95, 727–748. Google Scholar CrossRef Green Version
266. Kang, C.; LeRoith, D.; Gallagher, E.J. Diabetes, obesity, and breast cancer. Endocrinology2018, 159, 3801–3812. Google Scholar CrossRef Green Version
267. Pothuraju, R.; Rachagani, S.; Junker, W.M.; Chaudhary, S.; Saraswathi, V.; Kaur, S.; Batra, S.K. Pancreatic cancer associated with obesity and diabetes: An alternative approach for its targeting. J. Exp. Clin. Cancer Res.2018, 37, 319. Google Scholar CrossRef Green Version
268. Scully, T.; Ettela, A.; Gallagher, E.J.; LeRoith, D. Obesity, Type 2 Diabetes and Cancer Risk. Front. Oncol.2020, 10, 3196. Google Scholar
269. Perry, R.J.; Shulman, G.I. Mechanistic links between obesity, insulin, and cancer. Trends Cancer2020, 6, 75–78. Google Scholar CrossRef
270. Marques, R.G.; Fontaine, M.J.; Rogers, J. C-peptide: Much more than a byproduct of insulin biosynthesis. Pancreas2004, 29, 231–238. Google Scholar CrossRef PubMed
271. Jenab, M.; Riboli, E.; Cleveland, R.J.; Norat, T.; Rinaldi, S.; Nieters, A.; Biessy, C.; Tjønneland, A.; Olsen, A.; Overvad, K. Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer2007, 121, 368–376. Google Scholar CrossRef
272. Ma, J.; Li, H.; Giovannucci, E.; Mucci, L.; Qiu, W.; Nguyen, P.L.; Gaziano, J.M.; Pollak, M.; Stampfer, M.J. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: A long-term survival analysis. Lancet Oncol.2008, 9, 1039–1047. Google Scholar CrossRef Green Version
273. Bloomgarden, Z. Diabetes and cancer. Diabetes Care2001, 24, 780–781. Google Scholar
274. Bloomgarden, Z.T. Second world congress on the insulin resistance syndrome. Diabetes Care2005, 28, 1518–1523. Google Scholar CrossRef Green Version
275. Richardson, L.C.; Pollack, L.A. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat. Clin. Pract. Oncol.2005, 2, 48–53. Google Scholar CrossRef
276. Bertoni, A.G.; Saydah, S.; Brancati, F.L. Diabetes and the risk of infection-related mortality in the US. Diabetes Care2001, 24, 1044–1049. Google Scholar CrossRef PubMed Green Version
277. Theodoulou, M.; Seidman, A.D. Seminars in Oncology. In Cardiac Effects of Adjuvant Therapy for Early Breastcancer; Elsevier: Amsterdam, The Netherlands, 2003; pp. 730–739. Google Scholar
278. Wildiers, H.; Highley, M.S.; de Bruijn, E.A.; van Oosterom, A.T. Pharmacology of anticancer drugs in the elderly population. Clin. Pharmacokinet.2003, 42, 1213–1242. Google Scholar CrossRef PubMed
279. Nichols, C.R. Testicular cancer. Curr. Probl. Cancer1998, 22, 187–274. Google Scholar CrossRef
280. Donnelly, R.; Emslie-Smith, A.M.; Gardner, I.D.; Morris, A.D. Vascular complications of diabetes. BMJ2000, 320, 1062–1066. Google Scholar CrossRef PubMed
281. Flatters, S.J.; Bennett, G.J. Ethosuximide reverses paclitaxel-and vincristine-induced painful peripheral neuropathy. Pain2004, 109, 150–161. Google Scholar CrossRef
282. Bonadonna, G.; Valagussa, P. Dose-response effect of adjuvant chemotherapy in breast cancer. N. Engl. J. Med.1981, 304, 10–15. Google Scholar CrossRef PubMed
283. DeVita, V.T.; Hubbard, S.M.; Longo, D.L. The chemotherapy of lymphomas: Looking back, moving forward—the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res.1987, 47, 5810–5824. Google Scholar
284. Childs, B.B.; Cypress, M.; Spollett, G. Complete Nurse’s Guide to Diabetes Care; American Diabetes Association: Arlington County, VI, USA, 2017. Google Scholar
285. Clement, S.; Braithwaite, S.; Magee, M.; Ahmann, A.; Smith, E.; Schafer, R.; Hirsch, I. Erratum: Management of diabetes and hyperglycemia in hospitals (Technical Review). Diabetes Care2004, 27, 553–591. Google Scholar CrossRef PubMed Green Version
286. Jiralerspong, S.; Palla, S.L.; Giordano, S.H.; Meric-Bernstam, F.; Liedtke, C.; Barnett, C.M.; Hsu, L.; Hung, M.-C.; Hortobagyi, G.N.; Gonzalez-Angulo, A.M. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol.2009, 27, 3297. Google Scholar CrossRef PubMed Green Version
287. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin.2015, 65, 5–29. Google Scholar CrossRef PubMed
288. Tan, B.X.; Yao, W.X.; Ge, J.; Peng, X.C.; Du, X.B.; Zhang, R.; Yao, B.; Xie, K.; Li, L.H.; Dong, H. Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer2011, 117, 5103–5111. Google Scholar CrossRef PubMed
289. Volgi, J.R.; Baldwin, D., Jr. Glucocorticoid therapy and diabetes management. Nurs. Clin. N. Am.2001, 36, 333–339. Google Scholar
290. Braithwaite, S.S.; Barr, W.G.; Rahman, A.; Quddusi, S. Managing diabetes during glucocorticoid therapy: How to avoid metabolic emergencies. Postgrad. Med.1998, 104, 163–176. Google Scholar CrossRef
291. Hirsch, I.; Braithwaite, S.; Verderese, C. Practical Management of Inpatient Hyperglycemia; LakevilleConn Hilliard Publishing: Lakeville, CT, USA, 2005; pp. 1–41. Google Scholar
292. Trence, D.L. Management of patients on chronic glucocorticoid therapy: An endocrine perspective. Prim. Care Clin. Off. Pract.2003, 30, 593–605. Google Scholar CrossRef
293. McCoubrie, R.; Jeffrey, D.; Paton, C.; Dawes, L. Managing diabetes mellitus in patients with advanced cancer: A case note audit and guidelines. Eur. J. Cancer Care2005, 14, 244–248. Google Scholar CrossRef
294. Medina-Bolivar, F.; Condori, J.; Rimando, A.M.; Hubstenberger, J.; Shelton, K.; O’Keefe, S.F.; Bennett, S.; Dolan, M.C. Production and secretion of resveratrol in hairy root cultures of peanut. Phytochemistry2007, 68, 1992–2003. Google Scholar CrossRef
295. Tian, B.; Liu, J. Resveratrol: A review of plant sources, synthesis, stability, modification and food application. J. Sci. Food Agric.2020, 100, 1392–1404. Google Scholar CrossRef
296. Lançon, A.; Hanet, N.; Jannin, B.; Delmas, D.; Heydel, J.-M.; Lizard, G.; Chagnon, M.-C.; Artur, Y.; Latruffe, N. Resveratrol in human hepatoma HepG2 cells: Metabolism and inducibility of detoxifying enzymes. Drug Metab. Dispos.2007, 35, 699–703. Google Scholar CrossRef PubMed Green Version
297. Jeandet, P.; Douillet-Breuil, A.-C.; Bessis, R.; Debord, S.; Sbaghi, M.; Adrian, M. Phytoalexins from the Vitaceae: Biosynthesis, phytoalexin gene expression in transgenic plants, antifungal activity, and metabolism. J. Agric. Food Chem.2002, 50, 2731–2741. Google Scholar CrossRef
298. Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A double-edged sword in health benefits. Biomedicines2018, 6, 91. Google Scholar CrossRef Green Version
299. Li, L.; Qiu, R.L.; Lin, Y.; Cai, Y.; Bian, Y.; Fan, Y.; Gao, X.J. Resveratrol suppresses human cervical carcinoma cell proliferation and elevates apoptosis via the mitochondrial and p53 signaling pathways. Oncol. Lett.2018, 15, 9845–9851. Google Scholar CrossRef Green Version
300. Li, D.; Wang, G.; Jin, G.; Yao, K.; Zhao, Z.; Bie, L.; Guo, Y.; Li, N.; Deng, W.; Chen, X. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int. J. Mol. Med.2019, 43, 630–640. Google Scholar CrossRef Green Version
301. Öztürk, Y.; Günaydın, C.; Yalçın, F.; Nazıroğlu, M.; Braidy, N. Resveratrol enhances apoptotic and oxidant effects of paclitaxel through TRPM2 channel activation in DBTRG glioblastoma cells. Oxid. Med. Cell. Longev.2019, 2019, 4619865. Google Scholar CrossRef
302. Hoca, M.; Becer, E.; Kabadayı, H.; Yücecan, S.; Vatansever, H.S. The effect of resveratrol and quercetin on epithelial-mesenchymal transition in pancreatic cancer stem cell. Nutr. Cancer2020, 72, 1231–1242. Google Scholar CrossRef
303. Zhao, Y.; Cao, Y.; Sun, J.; Liang, Z.; Wu, Q.; Cui, S.; Zhi, D.; Guo, S.; Zhen, Y.; Zhang, S. Anti-breast cancer activity of resveratrol encapsulated in liposomes. J. Mater. Chem. B2020, 8, 27–37. Google Scholar CrossRef
304. Alobaedi, O.H.; Talib, W.H.; Basheti, I.A. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pac. J. Trop. Med.2017, 10, 400–408. Google Scholar CrossRef PubMed
305. Ismail, N.; Abdel–Mottaleb, Y.; Ahmed, A.A.E.; El-Maraghy, N.N. Novel combination of thymoquinone and resveratrol enhances anticancer effect on hepatocellular carcinoma cell line. Future J. Pharm. Sci.2018, 4, 41–46. Google Scholar CrossRef
306. Rai, G.; Mishra, S.; Suman, S.; Shukla, Y. Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight. Phytomedicine2016, 23, 233–242. Google Scholar CrossRef
307. Zhang, A.J.; Rimando, A.M.; Mizuno, C.S.; Mathews, S.T. α-Glucosidase inhibitory effect of resveratrol and piceatannol. J. Nutr. Biochem.2017, 47, 86–93. Google Scholar CrossRef
308. Rimando, A.M.; Nagmani, R.; Feller, D.R.; Yokoyama, W. Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor α-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J. Agric. Food Chem.2005, 53, 3403–3407. Google Scholar CrossRef
309. Yang, D.K.; Kang, H.-S. Anti-diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats. Biomol. Ther.2018, 26, 130. Google Scholar CrossRef Green Version
310. Agarwal, A.; Kasinathan, A.; Ganesan, R.; Balasubramanian, A.; Bhaskaran, J.; Suresh, S.; Srinivasan, R.; Aravind, K.; Sivalingam, N. Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species–independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells. Nutr. Res.2018, 51, 67–81. Google Scholar CrossRef PubMed
311. Muangnoi, C.; Jithavech, P.; Ratnatilaka Na Bhuket, P.; Supasena, W.; Wichitnithad, W.; Towiwat, P.; Niwattisaiwong, N.; Haworth, I.S.; Rojsitthisak, P. A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin. Biosci. Biotechnol. Biochem.2018, 82, 1301–1308. Google Scholar CrossRef PubMed Green Version
312. Talib, W.H.; Al-Hadid, S.A.; Ali, M.B.W.; Al-Yasari, I.H.; Abd Ali, M.R. Role of curcumin in regulating p53 in breast cancer: An overview of the mechanism of action. Breast Cancer Targets Ther.2018, 10, 207. Google Scholar CrossRef Green Version
313. Ismail, N.I.; Othman, I.; Abas, F.; H Lajis, N.; Naidu, R. Mechanism of apoptosis induced by curcumin in colorectal cancer. Int. J. Mol. Sci.2019, 20, 2454. Google Scholar CrossRef Green Version
314. Kunnumakkara, A.B.; Bordoloi, D.; Padmavathi, G.; Monisha, J.; Roy, N.K.; Prasad, S.; Aggarwal, B.B. Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases. Br. J. Pharmacol.2017, 174, 1325–1348. Google Scholar CrossRef Green Version
315. Xu, X.-Y.; Meng, X.; Li, S.; Gan, R.-Y.; Li, Y.; Li, H.-B. Bioactivity, health benefits, and related molecular mechanisms of curcumin: Current progress, challenges, and perspectives. Nutrients2018, 10, 1553. Google Scholar CrossRef PubMed Green Version
316. Ahmed, K.; Zaidi, S.F.; Cui, Z.G.; Zhou, D.; Saeed, S.A.; Inadera, H. Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer. Oncol. Lett.2019, 18, 487–498. Google Scholar CrossRef Green Version
317. Su, P.; Yang, Y.; Wang, G.; Chen, X.; Ju, Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int. J. Oncol.2018, 53, 1343–1353. Google Scholar CrossRef PubMed
318. Villegas, I.; Sánchez-Fidalgo, S.; de la Lastra, C.A. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol. Nutr. Food Res.2011, 55, 259–267. Google Scholar CrossRef PubMed
319. Jung, E.M.; Lim, J.H.; Lee, T.J.; Park, J.-W.; Choi, K.S.; Kwon, T.K. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis2005, 26, 1905–1913. Google Scholar CrossRef PubMed Green Version
320. Babushkina, E.A.; Belokopytova, L.V.; Grachev, A.M.; Meko, D.M.; Vaganov, E.A. Variation of the hydrological regime of Bele-Shira closed basin in Southern Siberia and its reflection in the radial growth of Larix sibirica. Reg. Environ. Chang.2017, 17, 1725–1737. Google Scholar CrossRef Green Version
321. Song, G.; Mao, Y.; Cai, Q.; Yao, L.; Ouyang, G.; Bao, S. Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression. Braz. J. Med. Biol. Res.2005, 38, 1791–1798. Google Scholar CrossRef Green Version
322. Sun, Y.; Liu, L.; Wang, Y.; He, A.; Hu, H.; Zhang, J.; Han, M.; Huang, Y. Curcumin inhibits the proliferation and invasion of MG-63 cells through inactivation of the p-JAK2/p-STAT3 pathway. Oncotargets Ther.2019, 12, 2011. Google Scholar CrossRef Green Version
323. Tomeh, M.A.; Hadianamrei, R.; Zhao, X. A review of curcumin and its derivatives as anticancer agents. Int. J. Mol. Sci.2019, 20, 1033. Google Scholar CrossRef PubMed Green Version
324. Den Hartogh, D.J.; Gabriel, A.; Tsiani, E. Antidiabetic properties of curcumin I: Evidence from in vitro studies. Nutrients2020, 12, 118. Google Scholar CrossRef Green Version
325. Den Hartogh, D.J.; Gabriel, A.; Tsiani, E. Antidiabetic properties of curcumin II: Evidence from in vivo studies. Nutrients2020, 12, 58. Google Scholar CrossRef Green Version
326. Abdelsamia, E.M.; Khaleel, S.A.; Balah, A.; Baky, N.A.A. Curcumin augments the cardioprotective effect of metformin in an experimental model of type I diabetes mellitus; Impact of Nrf2/HO-1 and JAK/STAT pathways. Biomed. Pharmacother.2019, 109, 2136–2144. Google Scholar CrossRef
327. Dajani, E.; Shahwan, T.; Dajani, N. Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): A complementary drug with historical and clinical significance. J. Physiol. Pharm.2016, 67, 801–817. Google Scholar
328. Younus, H. Molecular and Therapeutic: Actions of Thymoquinone; Springer: Berlin/Heidelberg, Germany, 2018. Google Scholar
329. Ahmad, A.; Husain, A.; Mujeeb, M.; Khan, S.A.; Najmi, A.K.; Siddique, N.A.; Damanhouri, Z.A.; Anwar, F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac. J. Trop. Biomed.2013, 3, 337–352. Google Scholar CrossRef Green Version
330. Aslan, M.; Afşar, E.; Kırımlıoglu, E.; Çeker, T.; Yılmaz, Ç. Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress. Nutr. Cancer2020, 73, 460–472. Google Scholar CrossRef PubMed
331. Darakhshan, S.; Pour, A.B.; Colagar, A.H.; Sisakhtnezhad, S. Thymoquinone and its therapeutic potentials. Pharmacol. Res.2015, 95, 138–158. Google Scholar CrossRef PubMed
332. Laskar, A.A.; Khan, M.A.; Askari, F.; Younus, H. Thymoquinone binds and activates human salivary aldehyde dehydrogenase: Potential therapy for the mitigation of aldehyde toxicity and maintenance of oral health. Int. J. Biol. Macromol.2017, 103, 99–110. Google Scholar CrossRef
333. Motaghed, M.; Al-Hassan, F.M.; Hamid, S.S. Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7. Pharmacogn. Res.2013, 5, 200. Google Scholar
334. El-Sheikh, A.A.; Morsy, M.A.; Abdalla, A.M.; Hamouda, A.H.; Alhaider, I.A. Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats. Mediat. Inflamm.2015, 2015, 859383. Google Scholar CrossRef Green Version
335. Kundu, J.; Choi, B.Y.; Jeong, C.-H.; Kundu, J.K.; Chun, K.-S. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2-and Src-mediated phosphorylation of EGF receptor tyrosine kinase. Oncol. Rep.2014, 32, 821–828. Google Scholar CrossRef PubMed Green Version
336. Woo, C.C.; Loo, S.Y.; Gee, V.; Yap, C.W.; Sethi, G.; Kumar, A.P.; Tan, K.H.B. Anticancer activity of thymoquinone in breast cancer cells: Possible involvement of PPAR-γ pathway. Biochem. Pharmacol.2011, 82, 464–475. Google Scholar CrossRef PubMed
337. Talib, W.H. Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci. Pharm.2017, 85, 27. Google Scholar CrossRef Green Version
338. Pelegrin, S.; Galtier, F.; Chalançon, A.; Gagnol, J.P.; Barbanel, A.M.; Pélissier, Y.; Larroque, M.; Lepape, S.; Faucanié, M.; Gabillaud, I. Effects of Nigella sativa seeds (black cumin) on insulin secretion and lipid profile: A pilot study in healthy volunteers. Br. J. Clin. Pharmacol.2019, 85, 1607–1611. Google Scholar CrossRef
339. Khalil, P.; Masood, S.; Rehman, A.U.; Khalil, F.; Nawaf, J. Preventive Role of Thymoquinone against Certain Chronic Health Issues: A Review. Int. J. Nutr. Sci.2020. Google Scholar CrossRef
340. Durvasula, R.V.; Petermann, A.T.; Hiromura, K.; Blonski, M.; Pippin, J.; Mundel, P.; Pichler, R.; Griffin, S.; Couser, W.G.; Shankland, S.J. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int.2004, 65, 30–39. Google Scholar CrossRef Green Version
341. Montazeri, R.S.; Fatahi, S.; Sohouli, M.H.; Abu-Zaid, A.; Santos, H.O.; Găman, M.A.; Shidfar, F. The effect of nigella sativa on biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials. J. Food Biochem.2021, e13625. Google Scholar CrossRef
342. Lambert, J.D.; Lee, M.J.; Lu, H.; Meng, X.; Hong, J.J.; Seril, D.N.; Sturgill, M.G.; Yang, C.S. Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice. J. Nutr.2003, 133, 4172–4177. Google Scholar CrossRef
343. Nagle, D.G.; Ferreira, D.; Zhou, Y.-D. Epigallocatechin-3-gallate (EGCG): Chemical and biomedical perspectives. Phytochemistry2006, 67, 1849–1855. Google Scholar CrossRef Green Version
344. Rodríguez-Carrasco, Y.; Gaspari, A.; Graziani, G.; Santini, A.; Ritieni, A. Fast analysis of polyphenols and alkaloids in cocoa-based products by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS). Food Res. Int.2018, 111, 229–236. Google Scholar CrossRef
345. Chopade, V.; Phatak, A.; Upaganlawar, A.; Tankar, A. Green tea (Camellia sinensis): Chemistry, traditional, medicinal uses and its pharmacological activities-a review. Pharmacogn. Rev.2008, 2, 157. Google Scholar
346. Katiyar, S.K.; Elmets, C.A. Green tea polyphenolic antioxidants and skin photoprotection. Int. J. Oncol.2001, 18, 1307–1313. Google Scholar CrossRef
347. Musial, C.; Kuban-Jankowska, A.; Gorska-Ponikowska, M. Beneficial Properties of Green Tea Catechins. Int. J. Mol. Sci.2020, 21, 1744. Google Scholar CrossRef PubMed Green Version
348. Wang, Y.-Q.; Lu, J.-L.; Liang, Y.-R.; Li, Q.-S. Suppressive effects of EGCG on cervical cancer. Molecules2018, 23, 2334. Google Scholar CrossRef Green Version
349. Ho, H.C.; Huang, C.C.; Lu, Y.T.; Yeh, C.M.; Ho, Y.T.; Yang, S.F.; Hsin, C.H.; Lin, C.W. Epigallocatechin-3-gallate inhibits migration of human nasopharyngeal carcinoma cells by repressing MMP-2 expression. J. Cell. Physiol.2019, 234, 20915–20924. Google Scholar CrossRef PubMed
350. Pal, D.; Sur, S.; Roy, R.; Mandal, S.; Kumar Panda, C. Epigallocatechin gallate in combination with eugenol or amarogentin shows synergistic chemotherapeutic potential in cervical cancer cell line. J. Cell. Physiol.2019, 234, 825–836. Google Scholar CrossRef PubMed Green Version
351. Yuan, C.H.; Horng, C.T.; Lee, C.F.; Chiang, N.N.; Tsai, F.J.; Lu, C.C.; Chiang, J.H.; Hsu, Y.M.; Yang, J.S.; Chen, F.A. Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling. Environ. Toxicol.2017, 32, 845–855. Google Scholar CrossRef PubMed
352. Chuu, C.-P.; Chen, R.-Y.; Kokontis, J.M.; Hiipakka, R.A.; Liao, S. Suppression of androgen receptor signaling and prostate specific antigen expression by (−)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett.2009, 275, 86–92. Google Scholar CrossRef PubMed Green Version
353. Xu, L.; Li, W.; Chen, Z.; Guo, Q.; Wang, C.; Santhanam, R.K.; Chen, H. Inhibitory effect of epigallocatechin-3-O-gallate on α-glucosidase and its hypoglycemic effect via targeting PI3K/AKT signaling pathway in L6 skeletal muscle cells. Int. J. Biol. Macromol.2019, 125, 605–611. Google Scholar CrossRef
354. Lin, Y.; Shi, D.; Su, B.; Wei, J.; Găman, M.A.; Sedanur Macit, M.; Borges do Nascimento, I.J.; Guimaraes, N.S. The effect of green tea supplementation on obesity: A systematic review and dose–response meta-analysis of randomized controlled trials. Phytother. Res.2020, 34, 2459–2470. Google Scholar CrossRef
355. Lanzotti, V. The analysis of onion and garlic. J. Chromatogr. A2006, 1112, 3–22. Google Scholar CrossRef Green Version
356. Chen, H.; Zhu, B.; Zhao, L.; Liu, Y.; Zhao, F.; Feng, J.; Jin, Y.; Sun, J.; Geng, R.; Wei, Y. Allicin inhibits proliferation and invasion in vitro and in vivo via SHP-1-mediated STAT3 signaling in cholangiocarcinoma. Cell. Physiol. Biochem.2018, 47, 641–653. Google Scholar CrossRef
357. Huang, W.L.; Wu, S.F.; Xu, S.T.; Ma, Y.C.; Wang, R.; Jin, S.; Zhou, S. Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF-κB signaling pathway. J. Food Sci.2020, 85, 1924–1931. Google Scholar CrossRef
358. Yang, Z.; Du, J.; Zhu, J.; Rong, Y.; Chen, S.; Yu, L.; Deng, X.; Zhang, X.; Sheng, H.; Yang, L. Allicin Inhibits Proliferation by Decreasing IL-6 and IFN-β in HCMV-Infected Glioma Cells. Cancer Manag. Res.2020, 12, 7305. Google Scholar CrossRef
359. Schultz, C.R.; Gruhlke, M.C.; Slusarenko, A.J.; Bachmann, A.S. Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells. J. Nat. Prod.2020, 83, 2518–2527. Google Scholar CrossRef PubMed
360. Jobani, B.M.; Najafzadeh, N.; Mazani, M.; Arzanlou, M.; Vardin, M.M. Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+ versus CD117+ melanoma cells. Phytomedicine2018, 48, 161–169. Google Scholar CrossRef PubMed
361. Țigu, A.B.; Toma, V.-A.; Moț, A.C.; Jurj, A.; Moldovan, C.S.; Fischer-Fodor, E.; Berindan-Neagoe, I.; Pârvu, M. The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells. Molecules2020, 25, 1947. Google Scholar CrossRef PubMed
362. Arellano-Buendía, A.S.; Castañeda-Lara, L.G.; Loredo-Mendoza, M.L.; García-Arroyo, F.E.; Rojas-Morales, P.; Argüello-García, R.; Juárez-Rojas, J.G.; Tapia, E.; Pedraza-Chaverri, J.; Sánchez-Lozada, L.G. Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes. Antioxidants2020, 9, 1134. Google Scholar CrossRef
363. Mandal, S.K.; Das, A.; Dey, S.; Sahoo, U.; Bose, S.; Bose, A.; Dhiman, N.; Madan, S.; Ramadan, M.A. Bioactivities of Allicin and related organosulfur compounds from garlic: Overview of the literature since 2010. Egypt. J. Chem.2019, 62, 1–11. Google Scholar CrossRef
364. Li, L.; Sheng, X.; Zhao, S.; Zou, L.; Han, X.; Gong, Y.; Yuan, H.; Shi, L.; Guo, L.; Jia, T. Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia. Purinergic Signal.2017, 13, 559–568. Google Scholar CrossRef PubMed Green Version
365. Lu, P.; Zhao, X.; Cui, T. Full Length Research Paper Production of emodin from Aspergillus ochraceus at preparative scale. Afr. J. Biotechnol.2010, 9. Available online: https://www.ajol.info/index.php/ajb/article/view/77969 (accessed on 9 April 2021).
366. Shun-Hua, L.; Lin, L.; Ru-Nan, Y.; Liang, S.-D. Compounds of traditional Chinese medicine and neuropathic pain. Chin. J. Nat. Med.2020, 18, 28–35. Google Scholar
367. Talib, W.H.; Alsalahat, I.; Daoud, S.; Abutayeh, R.F.; Mahmod, A.I. Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation. Molecules2020, 25, 5319. Google Scholar CrossRef PubMed
368. Tang, T.; Yin, L.; Yang, J.; Shan, G. Emodin, an anthraquinone derivative from Rheum officinale Baill, enhances cutaneous wound healing in rats. Eur. J. Pharmacol.2007, 567, 177–185. Google Scholar CrossRef PubMed
369. Huang, H.-C.; Chang, J.-H.; Tung, S.-F.; Wu, R.-T.; Foegh, M.L.; Chu, S.-H. Immunosuppressive effect of emodin, a free radical generator. Eur. J. Pharmacol.1992, 211, 359–364. Google Scholar CrossRef
370. Huei-Chen, H.; Shu-Hsun, C.; Chao, P.-D.L. Vasorelaxants from Chinese herbs, emodin and scoparone, possess immunosuppressive properties. Eur. J. Pharmacol.1991, 198, 211–213. Google Scholar CrossRef
371. Kaneshiro, T.; Morioka, T.; Inamine, M.; Kinjo, T.; Arakaki, J.; Chiba, I.; Sunagawa, N.; Suzui, M.; Yoshimi, N. Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation. Eur. J. Pharmacol.2006, 553, 46–53. Google Scholar CrossRef
372. Zhu, S.; Wang, Y.; Wang, X.; Li, J.; Hu, F. Emodin inhibits ATP-induced IL-1β secretion, ROS production and phagocytosis attenuation in rat peritoneal macrophages via antagonizing P2X7 receptor. Pharm. Biol.2014, 52, 51–57. Google Scholar CrossRef PubMed
373. Hsu, S.-C.; Chung, J.-G. Anticancer potential of emodin. BioMedicine2012, 2, 108–116. Google Scholar CrossRef PubMed
374. Dong, X.; Fu, J.; Yin, X.; Cao, S.; Li, X.; Lin, L.; Huyiligeqi; Ni, J. Emodin: A review of its pharmacology, toxicity and pharmacokinetics. Phytother. Res.2016, 30, 1207–1218. Google Scholar CrossRef
375. Mukund, V.; Mukund, D.; Sharma, V.; Mannarapu, M.; Alam, A. Genistein: Its role in metabolic diseases and cancer. Crit. Rev. Oncol. Hematol.2017, 119, 13–22. Google Scholar CrossRef
376. Spagnuolo, C.; Russo, G.L.; Orhan, I.E.; Habtemariam, S.; Daglia, M.; Sureda, A.; Nabavi, S.F.; Devi, K.P.; Loizzo, M.R.; Tundis, R. Genistein and cancer: Current status, challenges, and future directions. Adv. Nutr.2015, 6, 408–419. Google Scholar CrossRef PubMed Green Version
377. Chodon, D.; Banu, S.M.; Padmavathi, R.; Sakthisekaran, D. Inhibition of cell proliferation and induction of apoptosis by genistein in experimental hepatocellular carcinoma. Mol. Cell. Biochem.2007, 297, 73. Google Scholar CrossRef PubMed
378. Tatsuta, M.; Iishi, H.; Baba, M.; Yano, H.; Uehara, H.; Nakaizumi, A. Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine in Wistar rats. Int. J. Cancer1999, 80, 396–399. Google Scholar CrossRef
379. Estrela, J.M.; Mena, S.; Obrador, E.; Benlloch, M.; Castellano, G.; Salvador, R.; Dellinger, R.W. Polyphenolic phytochemicals in cancer prevention and therapy: Bioavailability versus bioefficacy. J. Med. Chem.2017, 60, 9413–9436. Google Scholar CrossRef
380. Yousefi, H.; Alihemmati, A.; Karimi, P.; Alipour, M.R.; Habibi, P.; Ahmadiasl, N. Effect of genistein on expression of pancreatic SIRT1, inflammatory cytokines and histological changes in ovariectomized diabetic rat. Iran. J. Basic Med. Sci.2017, 20, 423. Google Scholar
381. Luo, J.; Wang, A.; Zhen, W.; Wang, Y.; Si, H.; Jia, Z.; Alkhalidy, H.; Cheng, Z.; Gilbert, E.; Xu, B. Phytonutrient genistein is a survival factor for pancreatic β-cells via GPR30-mediated mechanism. J. Nutr. Biochem.2018, 58, 59–70. Google Scholar CrossRef
382. Talib, W.H.; Al Kury, L.T. Parthenolide inhibits tumor-promoting effects of nicotine in lung cancer by inducing P53-dependent apoptosis and inhibiting VEGF expression. Biomed. Pharmacother.2018, 107, 1488–1495. Google Scholar CrossRef
383. Williams, B.; Lees, F.; Tsangari, H.; Hutchinson, M.; Perilli, E.; Crotti, T. Assessing the Effects of Parthenolide on Inflammation, Bone Loss, and Glial Cells within a Collagen Antibody-Induced Arthritis Mouse Model. Mediat. Inflamm.2020, 2020, 6245798. Google Scholar CrossRef PubMed
384. Aljancic, I.; Vajs, V.; Bulatovic, V.; Menkovic, N.; Milosavljevic, S. Parthenolide from the aerial parts of Tanacetum larvatum. Biochem. Syst. Ecol.2001, 29, 655–658. Google Scholar CrossRef
385. Che, S.-T.; Bie, L.; Li, X.; Qi, H.; Yu, P.; Zuo, L. Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells. Int. J. Ophthalmol.2019, 12, 1531. Google Scholar CrossRef PubMed
386. Tadić, V.; Živković, J.; Bigović, D.; Žugić, A. Variation of parthenolide and phenolic compounds content in different parts of Tanacetum parthenium (L.) Schulz Bip. Asteraceae during 18 months storage. Lek. Sirovine2019, 35–39. Google Scholar CrossRef Green Version
387. Pajak, B.; Gajkowska, B.; Orzechowski, A. Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells. Folia Histochem. Cytobiol.2008, 46, 129–135. Google Scholar CrossRef PubMed Green Version
388. Kim, J.-H.; Liu, L.; Lee, S.-O.; Kim, Y.-T.; You, K.-R.; Kim, D.-G. Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res.2005, 65, 6312–6320. Google Scholar CrossRef PubMed Green Version
389. Carlisi, D.; Buttitta, G.; Di Fiore, R.; Scerri, C.; Drago-Ferrante, R.; Vento, R.; Tesoriere, G. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis. Cell Death Dis.2016, 7, e2194. Google Scholar CrossRef PubMed Green Version
390. Nakabayashi, H.; Shimizu, K. Involvement of Akt/NF-κB pathway in antitumor effects of parthenolide on glioblastoma cells in vitro and in vivo. BMC Cancer2012, 12, 1–11. Google Scholar CrossRef Green Version
391. Yip-Schneider, M.T.; Wu, H.; Stantz, K.; Agaram, N.; Crooks, P.A.; Schmidt, C.M. Dimethylaminoparthenolide and gemcitabine: A survival study using a genetically engineered mouse model of pancreatic cancer. BMC Cancer2013, 13, 194. Google Scholar CrossRef Green Version
392. Hao, Q.; Wang, B.; Zhang, W.; Qiu, W.; Liu, Q.; Li, X. NF-κB inhibitor parthenolide promotes renal tubules albumin uptake in type 2 diabetic nephropathy. Chin. Med. Sci. J.2020, 35, 31–42. Google Scholar
393. Kim, C.Y.; Kang, B.; Hong, J.; Choi, H.-S. Parthenolide inhibits lipid accumulation via activation of Nrf2/Keap1 signaling during adipocyte differentiation. Food Sci. Biotechnol.2020, 29, 431–440. Google Scholar CrossRef
394. Imran, M.; Rauf, A.; Abu-Izneid, T.; Nadeem, M.; Shariati, M.A.; Khan, I.A.; Imran, A.; Orhan, I.E.; Rizwan, M.; Atif, M. Luteolin, a flavonoid, as an anticancer agent: A review. Biomed. Pharmacother.2019, 112, 108612. Google Scholar CrossRef
395. Lim, S.H.; Jung, S.K.; Byun, S.; Lee, E.J.; Hwang, J.A.; Seo, S.G.; Kim, Y.A.; Yu, J.G.; Lee, K.W.; Lee, H.J. Luteolin suppresses UVB-induced photoageing by targeting JNK1 and p90RSK2. J. Cell. Mol. Med.2013, 17, 672–680. Google Scholar CrossRef
396. Wang, H.; Yang, L.; Zu, Y.; Zhao, X. Microwave-assisted simultaneous extraction of luteolin and apigenin from tree peony pod and evaluation of its antioxidant activity. Sci. World J.2014, 2014, 506971. Google Scholar CrossRef PubMed Green Version
397. Lin, D.; Kuang, G.; Wan, J.; Zhang, X.; Li, H.; Gong, X.; Li, H. Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncol. Rep.2017, 37, 895–902. Google Scholar CrossRef PubMed Green Version
398. Jiang, Z.-Q.; Li, M.-H.; Qin, Y.-M.; Jiang, H.-Y.; Zhang, X.; Wu, M.-H. Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of MicroRNA-34a-5p. Int. J. Mol. Sci.2018, 19, 447. Google Scholar CrossRef PubMed Green Version
399. Lee, Y.J.; Lim, T.; Han, M.S.; Lee, S.-H.; Baek, S.H.; Nan, H.-Y.; Lee, C. Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells. Oncol. Rep.2017, 37, 1219–1226. Google Scholar CrossRef Green Version
400. Yu, Q.; Zhang, M.; Ying, Q.; Xie, X.; Yue, S.; Tong, B.; Wei, Q.; Bai, Z.; Ma, L. Decrease of AIM2 mediated by luteolin contributes to non-small cell lung cancer treatment. Cell Death Dis.2019, 10, 1–14. Google Scholar CrossRef PubMed
401. Lin, Y.; Shi, R.; Wang, X.; Shen, H.-M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets2008, 8, 634–646. Google Scholar CrossRef
402. Horinaka, M.; Yoshida, T.; Shiraishi, T.; Nakata, S.; Wakada, M.; Nakanishi, R.; Nishino, H.; Matsui, H.; Sakai, T. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene2005, 24, 7180–7189. Google Scholar CrossRef Green Version
403. Cai, X.; Ye, T.; Liu, C.; Lu, W.; Lu, M.; Zhang, J.; Wang, M.; Cao, P. Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol. Vitr.2011, 25, 1385–1391. Google Scholar CrossRef
404. Ambasta, R.K.; Jha, S.K.; Kumar, D.; Sharma, R.; Jha, N.K.; Kumar, P. Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules. J. Transl. Med.2015, 13, 307. Google Scholar CrossRef
405. Ambasta, R.K.; Gupta, R.; Kumar, D.; Bhattacharya, S.; Sarkar, A.; Kumar, P. Can luteolin be a therapeutic molecule for both colon cancer and diabetes? Brief. Funct. Genom.2019, 18, 230–239. Google Scholar CrossRef
406. Rauf, A.; Imran, M.; Khan, I.A.; ur-Rehman, M.; Gilani, S.A.; Mehmood, Z.; Mubarak, M.S. Anticancer potential of quercetin: A comprehensive review. Phytother. Res.2018, 32, 2109–2130. Google Scholar CrossRef PubMed
407. Grande, F.; Parisi, O.I.; Mordocco, R.A.; Rocca, C.; Puoci, F.; Scrivano, L.; Quintieri, A.M.; Cantafio, P.; Ferla, S.; Brancale, A. Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization. Eur. J. Pharm. Sci.2016, 82, 161–170. Google Scholar CrossRef PubMed
408. Iacopetta, D.; Grande, F.; Caruso, A.; Mordocco, R.A.; Plutino, M.R.; Scrivano, L.; Ceramella, J.; Muià, N.; Saturnino, C.; Puoci, F. New insights for the use of quercetin analogs in cancer treatment. Future Med. Chem.2017, 9, 2011–2028. Google Scholar CrossRef PubMed
409. Kim, W.K.; Bang, M.H.; Kim, E.S.; Kang, N.E.; Jung, K.C.; Cho, H.J.; Park, J.H. Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J. Nutr. Biochem.2005, 16, 155–162. Google Scholar CrossRef
410. Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr.2006, 136, 2715–2721. Google Scholar CrossRef Green Version
411. Liao, H.; Bao, X.; Zhu, J.; Qu, J.; Sun, Y.; Ma, X.; Wang, E.; Guo, X.; Kang, Q.; Zhen, Y. O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway. Chem. Biol. Interact.2015, 242, 91–98. Google Scholar CrossRef
412. Ranganathan, S.; Halagowder, D.; Sivasithambaram, N.D. Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS ONE2015, 10, e0141370. Google Scholar CrossRef Green Version
413. Minaei, A.; Sabzichi, M.; Ramezani, F.; Hamishehkar, H.; Samadi, N. Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. Mol. Biol. Rep.2016, 43, 99–105. Google Scholar CrossRef
414. Chang, J.-H.; Lai, S.-L.; Chen, W.-S.; Hung, W.-Y.; Chow, J.-M.; Hsiao, M.; Lee, W.-J.; Chien, M.-H. Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways. Biochim. Biophys. Acta (BBA) Mol. Cell Res.2017, 1864, 1746–1758. Google Scholar CrossRef
415. Ali, H.; Dixit, S. Quercetin attenuates the development of 7, 12-dimethyl benz (a) anthracene (DMBA) and croton oil-induced skin cancer in mice. J. Biomed. Res.2015, 29, 139. Google Scholar
416. Bule, M.; Abdurahman, A.; Nikfar, S.; Abdollahi, M.; Amini, M. Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies. Food Chem. Toxicol.2019, 125, 494–502. Google Scholar CrossRef PubMed
417. Srinivasan, P.; Vijayakumar, S.; Kothandaraman, S.; Palani, M. Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J. Pharm. Anal.2018, 8, 109–118. Google Scholar CrossRef
418. An, Y.-W.; Jin, H.-T.; Yuan, B.; Wang, J.-C.; Wang, C.; Liu, H.-Q. Research progress of berberine mediated photodynamic therapy. Oncol. Lett.2021, 21, 1–10. Google Scholar CrossRef
419. Yun, D.; Yoon, S.Y.; Park, S.J.; Park, Y.J. The Anticancer Effect of Natural Plant Alkaloid Isoquinolines. Int. J. Mol. Sci.2021, 22, 1653. Google Scholar CrossRef
420. Xiong, P.; Niu, L.; Talaei, S.; Kord-Varkaneh, H.; Clark, C.C.; Găman, M.-A.; Rahmani, J.; Dorosti, M.; Mousavi, S.M.; Zarezadeh, M. The effect of berberine supplementation on obesity indices: A dose–response meta-analysis and systematic review of randomized controlled trials. Complement. Ther. Clin. Pract.2020, 39, 101113. Google Scholar CrossRef
421. Costea, T.; Hudiță, A.; Ciolac, O.-A.; Gălățeanu, B.; Ginghină, O.; Costache, M.; Ganea, C.; Mocanu, M.-M. Chemoprevention of colorectal cancer by dietary compounds. Int. J. Mol. Sci.2018, 19, 3787. Google Scholar CrossRef PubMed Green Version
422. Ramprasath, V.R.; Awad, A.B. Role of phytosterols in cancer prevention and treatment. J. Aoac Int.2015, 98, 735–738. Google Scholar CrossRef
423. Xiong, M.; Huang, Y.; Liu, Y.; Huang, M.; Song, G.; Ming, Q.; Ma, X.; Yang, J.; Deng, S.; Wen, Y. Antidiabetic activity of ergosterol from Pleurotus ostreatus in KK-Ay mice with spontaneous type 2 diabetes mellitus. Mol. Nutr. Food Res.2018, 62, 1700444. Google Scholar CrossRef
424. Oei, A.L.; Sweep, F.C.; Thomas, C.M.; Boerman, O.C.; Massuger, L.F. The use of monoclonal antibodies for the treatment of epithelial ovarian cancer. Int. J. Oncol.2008, 32, 1145–1157. Google Scholar CrossRef
425. Pourianezhad, F.; Tahmasebi, S.; Nikfar, S.; Mirhoseini, M.; Abdusi, V. Review on feverfew, a valuable medicinal plant. J. Herbmed Pharmacol.2016, 5. Google Scholar
426. Carlisi, D.; D’Anneo, A.; Angileri, L.; Lauricella, M.; Emanuele, S.; Santulli, A.; Vento, R.; Tesoriere, G. Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J. Cell. Physiol.2011, 226, 1632–1641. Google Scholar CrossRef PubMed
427. Godic, A.; Poljšak, B.; Adamic, M.; Dahmane, R. The role of antioxidants in skin cancer prevention and treatment. Oxid. Med. Cell. Longev.2014, 2014, 860479. Google Scholar CrossRef PubMed
428. Westerlund, A.; Steineck, G.; Bälter, K.; Stattin, P.; Grönberg, H.; Hedelin, M. Dietary supplement use patterns in men with prostate cancer: The Cancer Prostate Sweden study. Ann. Oncol.2011, 22, 967–972. Google Scholar CrossRef PubMed
429. Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and prevention of chronic disease. Crit. Rev. Food Sci. Nutr.2004, 44, 275–295. Google Scholar CrossRef
430. Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med.1994, 330, 1029–1035. Google Scholar CrossRef
431. Goodman, M.; Bostick, R.M.; Kucuk, O.; Jones, D.P. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radic. Biol. Med.2011, 51, 1068–1084. Google Scholar CrossRef
432. Middha, P.; Weinstein, S.J.; Männistö, S.; Albanes, D.; Mondul, A.M. β-carotene supplementation and lung cancer incidence in the alpha-tocopherol, Beta-carotene cancer prevention study: The role of tar and nicotine. Nicotine Tob. Res.2019, 21, 1045–1050. Google Scholar CrossRef Green Version
433. Narita, S.; Saito, E.; Sawada, N.; Shimazu, T.; Yamaji, T.; Iwasaki, M.; Ishihara, J.; Takachi, R.; Shibuya, K.; Inoue, M. Dietary consumption of antioxidant vitamins and subsequent lung cancer risk: The J apan P ublic H ealth C enter-based prospective study. Int. J. Cancer2018, 142, 2441–2460. Google Scholar CrossRef Green Version
434. Klein, E.A.; Thompson, I.M.; Tangen, C.M.; Crowley, J.J.; Lucia, M.S.; Goodman, P.J.; Minasian, L.M.; Ford, L.G.; Parnes, H.L.; Gaziano, J.M. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA2011, 306, 1549–1556. Google Scholar CrossRef
435. Sayin, V.I.; Ibrahim, M.X.; Larsson, E.; Nilsson, J.A.; Lindahl, P.; Bergo, M.O. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med.2014, 6, 221ra15. Google Scholar CrossRef
436. Wiel, C.; Le Gal, K.; Ibrahim, M.X.; Jahangir, C.A.; Kashif, M.; Yao, H.; Ziegler, D.V.; Xu, X.; Ghosh, T.; Mondal, T. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell2019, 178, 330–345. Google Scholar CrossRef PubMed
437. Le Gal, K.; Ibrahim, M.X.; Wiel, C.; Sayin, V.I.; Akula, M.K.; Karlsson, C.; Dalin, M.G.; Akyürek, L.M.; Lindahl, P.; Nilsson, J. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med.2015, 7, 308re8. Google Scholar CrossRef PubMed
438. Vyas, S.; Zaganjor, E.; Haigis, M.C. Mitochondria and cancer. Cell2016, 166, 555–566. Google Scholar CrossRef PubMed
439. Piskounova, E.; Agathocleous, M.; Murphy, M.M.; Hu, Z.; Huddlestun, S.E.; Zhao, Z.; Leitch, A.M.; Johnson, T.M.; DeBerardinis, R.J.; Morrison, S.J. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature2015, 527, 186–191. Google Scholar CrossRef PubMed Green Version
440. Heaney, M.L.; Gardner, J.R.; Karasavvas, N.; Golde, D.W.; Scheinberg, D.A.; Smith, E.A.; O’Connor, O.A. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res.2008, 68, 8031–8038. Google Scholar CrossRef PubMed Green Version
441. Fukui, M.; Yamabe, N.; Zhu, B.T. Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur. J. Cancer2010, 46, 1882–1891. Google Scholar CrossRef PubMed Green Version
442. Li, N.; Sun, C.; Zhou, B.; Xing, H.; Ma, D.; Chen, G.; Weng, D. Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS ONE2014, 9, e100314. Google Scholar CrossRef
443. Wu, Y.J.; Muldoon, L.L.; Neuwelt, E.A. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J. Pharmacol. Exp. Ther.2005, 312, 424–431. Google Scholar CrossRef Green Version Figure 1. Cancer altered metabolism. G6P, glucose-6-phosphate; LDH, lactate dehydrogenase enzyme; α-KG, alpha-ketoglutarate. Created using Biorender software. Figure 1. Cancer altered metabolism. G6P, glucose-6-phosphate; LDH, lactate dehydrogenase enzyme; α-KG, alpha-ketoglutarate. Created using Biorender software.Figure 2. Metabolic link between diabetes and cancer. (→), activation; (┬), inhibition; IR, insulin receptor; IGF-R, insulin-like growth factor receptor; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, rapamycin signaling pathway; GH, growth hormone; IGF-1, insulin-like growth factor 1; HIF-α, hypoxia-inducible factor-1α; GLUT, glucose receptor; PKC-α, protein kinase C; PPAR, peroxisome proliferator-activated receptor; EGF, epithelial growth factor; PDH, prolyl hydroxylase; NADPH, nicotinamide adenine dinucleotide phosphate; ETM, epithelial to mesenchymal trasition; ROS, reactive oxygen species; SOD, superoxide dismutase. Created using Biorender software. Figure 2. Metabolic link between diabetes and cancer. (→), activation; (┬), inhibition; IR, insulin receptor; IGF-R, insulin-like growth factor receptor; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, rapamycin signaling pathway; GH, growth hormone; IGF-1, insulin-like growth factor 1; HIF-α, hypoxia-inducible factor-1α; GLUT, glucose receptor; PKC-α, protein kinase C; PPAR, peroxisome proliferator-activated receptor; EGF, epithelial growth factor; PDH, prolyl hydroxylase; NADPH, nicotinamide adenine dinucleotide phosphate; ETM, epithelial to mesenchymal trasition; ROS, reactive oxygen species; SOD, superoxide dismutase. Created using Biorender software.Table 1. Various definitions of metabolic syndrome. Table 1. Various definitions of metabolic syndrome.| Risk Factors | NCEP/ATP III | WHO 1999 | IDF | |:-:|:-:|:-:|:-:| | (3 of 5 criteria necessary)41,42 | (impaired glucose regulation or hyperinsulinemia and 2 or more criteria necessary) A | (increased waist circumference plus any 2 of other 4 criteria) 50 | | Fasting glucose | ≥110 mg/dL | ≥110 mg/dL | ≥110 mg/dL | | Prandial glucose | | >140 mg/dL | | | Hyperinsulinemia | | Fasting serum insulin: third quartile for the control group | | | Hypertriglyceridemia B | ≥150 mg/dL | ≥150 mg/dL | ≥150 mg/dL | | Low HDL-C | <40 mg/dL<50 mg/dL | <35 mg/dL<39 mg/dL | <40 mg/dL<50 mg/dL | | MenWomen | | Abdominal obesity | >102 cm>88 cm | waist: hip ratio>0.9 in>0.85 in | ≥94 cm≥80 cm | | MenWomen | | Hypertension B | ≥130/≥85 mm Hg | ≥140/≥90 mm Hg | ≥130/≥85 mm | | Micro-albuminuria | | ≥20 μg/min | |

A World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva, Switzerland: World Health Organization, 1999. B Considered positive criteria if a person is on medications for lipids, hypertension, or hyperglycemia regardless of value. Abbreviations: NCEP/ATP III, National Cholesterol Education Program/Adult Treatment Panel III; WHO, World Health Organization; IDF, International Diabetes Federation; HDL, high-density lipoprotein.Table 2. Antidiabetic and anticancer activity of some natural products that have the ability to treat both diseases. Table 2. Antidiabetic and anticancer activity of some natural products that have the ability to treat both diseases.| Natural Products | Mechanism of Action in Cancer | Mechanism of Action in Diabetes | |:-:|:–|:–| | Resveratrol | ↑ caspase-3 and caspase-9, p53, X-associated protein Bcl-2 in human cervical carcinoma 141↓ signaling pathway of AKT/STAT3 in colon cancer cells 142↑ TRPM2 channel in glioblastoma cells 143control the expressions of vimentin, CTA-2, IL-1β, TNF- α, and N-cadherin in pancreatic cancer cells 144↑ Bcl-2 activity, p53, Bax, and caspase expression in breast cancer 145↓ tumor volume in Ehrlich ascites carcinoma cells 148 | ↓ α-glucosidase, carbohydrate absorption, and post-prandial blood glucose response in mice 149↑ muscle and liver glucose absorption ↓ adipose tissue and liver inflammation↑ adaptive thermogenesis capability↓ pancreatic insulin secretion, and mimic caloric restriction effects 149↑ serum blood glucose, insulin level, and dyslipidemia in diabetic rats 151 | | Curcumin | ↑ apoptotic ligand-inducing tumor-necrosis-factor-related apoptosis (TRAIL) pathways ↑ death receptor factor 5in HT-29 and HCT-116 colon cancer cells 161↑ Fas-mediated apoptotic pathway, caspase 8 activation, Bax expression↓ Bcl-2 in HT-29 colon cancer 162,163, and HCT-116 155↓ JAK/STAT signal in osteosarcoma 164interfere with nuclear factor κ (NFκB), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinase (MAPK) in prostate cancer 165 | ↑ adipocyte differentiation substantially, glucose levels, and the activity of human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding 166↓ glucose uptake, leptin levels, NF-kB p65 nuclear fraction, phospho-JNK1/2, phospho-IRS-1(S), MMP-2, MMP-9 and VEGF protein in 3T3-L1 adipocytes 166↓ levels of urinary enzymes (acid phosphatase, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)) 167↓ JAK/STAT signalling pathway ↓ myocardial degeneration, lipid peroxidation levels, IL-6, creatine kinase-MB (CK-MB), troponin I, and tumor growth factor-β1 (TGF-β1) in co-treatment with metformin 168 | | Thymoquinone | ↓ cell arrest at various stages in MCF-7 cell line 175↓ serum TNF- α, IL-6, and iNOS enzyme production and improve histopathological outputs in Wistar rats 176↓ phosphorylation of EGFR to tyrosine-1173 residues and JAK2 in HCT 116 177↑ cytotoxicity in the xenograft mouse model of breast cancer 178↑ apoptosis by reducing antiapoptotic protein expression 179 | ↓ blood glucose level, triglycerides and cholesterol concentrations↑ high-density lipoprotein, insulin sensitivity and pancreatic β-cell regeneration 180maintain the integrity of pancreatic β-cells by enhancing oxidative stress 181 | | EGCG | ↓ MMP-2 through modulation the Src signaling pathway in cervical cancer 190↓ cyclinD1 ↑ LIMD1, RBSP3, and p16 cell-cycle inhibitors at the G1/S cell cycle level in cervical cancer cell line 192↑ AKT/STAT3 pathway, apoptosis in cisplatin-resistant oral cancer cell 193 | ↓ α-glucosidase↑ glucose uptake↑ GLUT4 translocation to plasma membrane through PI3K/AKT signaling pathway in L6 skeletal muscle cells 195 | | Allicin | ↓ cell migration, STAT3↑ SHP-1, apoptosis in cholangiocarcinoma cell 198↓ signaling pathway of NF-κ in colorectal cancer 199↓ cytokine release ↑ p53 and radiotherapy sensitivity enhancement in glioma cells 200↑ apoptosis ↓ ornithine decarboxylase in neuroblastoma Cells. 201↓ MMP-9 mRNA expression ↑ cyclin D1 in melanoma cells 202 | ↑ insulin levels ↓ hyperglycemia, (GLUT4) and IRSs expression 204↑ Nrf2 ↓ Keap1, HIF-1α, SBP, and VEGF 204↓ autoantibodies and anti-islet cell antibodies (ICA) for type 1 diabetes (IDDM) 205 | | Emodin | ↑ apoptosis, cell cycle arrest, HIF-1α, glutathione phase I and II, and glutathione S-transferase P, N-acetyltransferase↓ angiogenesis, invasion, migration, formation of chemical-induced carcinogen-DNA adducts, HER2/neu, CKII kinase, and p34cdc2 kinase in human cancer cells 215↓ ERK phosphorylation in epithelial ovarian cancer 266 | ↓ cellular FLICE-inhibitory protein (cFLIP) and p38MAPK pathway↑ activate PPARγ pathway, and modulate AMPK signalling pathway 216 | | Genistein | ↓ proliferation, angiogenesis and metastasis↑ apoptosis leading to tumor growth reduction in hepatocellular and gastric cancer models of Wistar rats 219,220↓ COX-2-stimulating factors such as activated protein-1 (AP-1) and Nf-κB in pancreatic, colon, breast, and lung cancer 217 | modulate the proliferation of β-cells and the secretion of insulin 222↑ cAMP signaling, and the mass of islets in diabetic mice 223 | | Parthenolide | interrupt DNA replication 267↓ STAT3↑ apoptotic pathway 268↑ p53 and reactive oxygen species (ROS) 228↓ breast cancer stem-like cells by stimulating oxidative stress and necrosis 231↓ cell growth of glioblastoma cells 232 | ↓ inflammation and remodel the impaired insulin signaling pathway↑ cubilin and albumin uptake expression 234modulate reactive oxygen species production, and control the Nrf2- (Keap1) pathway 235↓ adipogenic factors (PPARc and C/EBPa) and its target protein FABP4 production 235 | | Luteolin | ↑ apoptosis pathways and death receptor 5 expression 244↑ JNK ↓ NF-κB, mediate the cellular growth inhibition and G2 arrest 245↓ proliferation, angiogenesis, VEGF receptor, PI3K/Akt and PI3K/p70S6 kinase pathways 246↓ cell proliferation and stimulate apoptosis in H460 and A549 cells 240,241,242 | regulate diabetes through mammalian target of rapamycin (mTOR), cytokine, AMPK, and p53 247 | | Quercetin | ↑ apoptosis↓epidermal growth factor receptor (EGFR) expression 251↑ caspase-3 and-9↓ Bcl-2, Bcl-xL 252↑ G1 phase arrest in breast cancer cell lines 253,254↓ cell invasion and migration↑ apoptosis in human lung carcinoma A549 cells 256 | ↓ serum glucose levelmodulate hepatic gene expressions↓ α-glucosidase activity, and PPAR-γ↑ insulin action 259 | | Berberine | ↓ survivin and Bcl2↑ apoptosis, p53, and Bax expression in gastric cancer cells 260↑ JNK phosphorylation, cytochrome c and AIF, and caspase-3↓ mitochondrial membrane potential, and Bcl-2 expression in breast cancer 261 | ↓ blood glucose↓ risk of metabolic syndrome, levels of hemoglobin A1C and triglyceride↓ leptin and resistin secretion↑ insulin sensitivity and weight loss ↑ lipid metabolism and mRNA expression of adiponectin 262 | | Phytosterols | ↓ cell growth and metastasis ↓ tumor size in athymic mice injected with MCF-7 cells 264 | ↑ GLUT4 translocation↑ PI3K/Akt and PKC pathways↓ fasting blood glucose levels 265 |

Table 3. Clinical trials conducted using combination treatment of antioxidants with chemotherapeutic agents. Table 3. Clinical trials conducted using combination treatment of antioxidants with chemotherapeutic agents.| Combination Treatment | Results | Ref. | |:-:|:-:|:-:| | Vitamin C + doxorubicin | Increased resistance to treatment in cell lines of chronic myelogenous leukemia (K562) and lymphoma (RL) | 282 | | Larger tumors in mice with RL cell xenografts | | Resveratrol + paclitaxel | Decreased antitumor action of paclitaxel in human breast tumor cells | 283 | | Quercetin at low doses + cisplatin, 5-FU, taxol or pirarubicin | Decreased efficiency of the treatment in athymic nude mice with ovarian tumor cells (C13*) xenografts | 284 | | N-acetylcysteine before or up to 1 h after the drug + cisplatin | Blockade of proapoptotic effect of cisplatin in human ovarian carcinoma cells (SKOV3), human SCLC tumor cells (B.5 LX-1), human glioblastoma cells (U87), and rat fibroblasts | 285 |

	Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Diabetes mellitus is a class of metabolic disorders characterized by prolonged periods of hyperglycemia. According to the World Health Organization (WHO), in the year 2014, 422 million people worldwide suffered from diabetes, and 1.6 million deaths were directly related to diabetes in the year 2016. Moreover, these statistics have been rising slowly over the last few decades 1. Diabetes mellitus (DM) is displayed as either type 1 diabetes mellitus (result from total insulin deficiency due to beta-cell death follow an autoimmune disease) or type 2 Diabetes Mellitus (predominantly resulting from insulin resistance, rendering target cells unable to effectively respond to insulin and so unable to utilize blood glucose for energy). It is well known that diabetes mellitus increases the risk of developing a variety of severe life-threatening health complications, resulting from the disruption and impairment in the function of several organs (kidneys, hearts, skin, blood vessels, or nerves), leading to both microvascular and macrovascular complications which include nephropathy, diabetic retinopathy, and neuropathy, as well as atherosclerosis, hypertension, and stroke. These diabetic vascular complications are responsible for the majority of mortality in diabetic patients 2. In addition to these complications, elevated blood glucose levels have been shown to stimulate cancer cell proliferation and progression 3. Studies have shown a strong correlation between diabetes mellitus and carcinogenesis and the most evident correlation is reported with type 2 diabetes mellitus (T2DM). Nevertheless, In type 1 diabetes mellitus (T1DM), the risk of carcinogenesis has also been identified but is less evident compared to that with T2DM 4. However, in both types of diabetes mellitus cancer incidence tends to be increased 5. Cancer is the second leading cause of death worldwide and in the year 2018, approximately 9.6 million deaths were attributed to cancer, and nearly one in six deaths around the world are caused by cancer 6. Both diabetes and cancer have a dramatic detrimental effect on both the mortality rate and the quality of life, and the simultaneous rise in incidence rates of both diseases has encouraged the research community to search into a possible correlation in terms of pathophysiological pathways and/or the common climate 7. Hyperglycemia causes epigenetic alterations by several mechanisms including DNA methylation and chromatin remodeling, resulting in abnormal gene expression. Moreover, in cancer, abnormal gene expression causes tumor growth by increasing the metastases, proliferation, and chemoresistance of cancer cells 8. The proliferation of cancer cells which is induced by hyperglycemia/diabetes occurs indirectly by mediating the following processes (1) insulin and insulin-like growth factor 1 (IGF-1), (2) secretion of leptin/adiponectin, (3) inflammatory responses, (4) production of reactive oxygen species (ROS; oxidative stress) and (5) immune abnormalities (platelet activation) 9. In addition to a direct correlation between impaired glucose tolerance/diabetes and the initiation of cancer, proliferation and invasiveness may occur due to hyperglycemia 10. Many epidemiological reports have shown that diabetes is positively associated with several types of cancers including breast, colorectal, endometrial, liver and pancreatic cancers. On the other hand, a decreased prevalence of prostate cancer has been observed in diabetic patients 11. Ben et al. found a significant association between DM and pancreatic with an inverse correlation between the duration of DM and the occurrence of pancreatic cancer in both sexes, thus observing the greatest risk of developing pancreatic cancer in patients with a duration of DM shorter than 1 year after diagnosis 12. Similar findings were observed in another study 13. Cancer risk in diabetic patients is 20% higher based on a meta-analysis of 20 studies 14. The analysis of data obtained by Hulda Hrund Bjornsdottir et al. on 450,000 people with type 2 diabetes and more than 2 million people without diabetes in Sweden between 1998 and 2014 was unable to show a cause-and-effect relationship. Nevertheless, people with blood sugar disease were observed to have a higher risk of developing several types of cancer including a 231% higher risk of hepatocellular cancer, a 119% higher risk of pancreatic cancer, and a 78% higher risk of uterine cancer compared to those without type 2 diabetes. Additionally, people with diabetes had an elevated risk of kidney cancer (45% higher), stomach cancer (21% higher), cancer of the gallbladder and bile duct (32% higher), and penile cancer (56% higher). Moreover, the incidence of colorectal cancer and bladder cancer was also 20% higher, while the breast cancer risk was 5% higher 15. Besides the increased risk of cancer by hyperglycemia/diabetes, several meta-analysis studies have also linked diabetes with a higher incidence of poor post-treatment prognosis in diabetic cancer subjects 16. In addition, the effect of hyperglycemia on breast cancer chemotherapy resistance have been shown in recent studies 17. Although epidemiological studies have shown that cancer mortality in diabetic patients is relatively increased, it is still unclear if this is a consequence of hyperglycemia and hyperinsulinemia (growth-promoting effect on cancer cells), poor health conditions attributable to diabetes comorbidity, or a combination of all these factors 18. There is strong evidence that cancer patients with diabetes are treated less aggressively or are expected to be less likely treated with modified anti-cancer therapy than non-diabetic cancer patients 19. Some anti-diabetic drugs, such as metformin, have been shown to reduce the incidence of cancer in diabetes patients, enhance the efficacy of anti-cancer drugs and also has shown favorable survival in cancer patients 16. This review presents a detailed discussion of the major metabolic changes in cancer cells that maintain their development. Furthermore, since diabetes is a metabolic syndrome we will discuss the metabolic linkage between diabetes and cancer. We also will describe therapeutic challenges facing treating diabetic patients with cancer and suggested therapies. Finally, we will explore various natural products that have the capacity to target both diseases and the mechanisms of action on both diseases. Generally, cancer cells have the ability to proliferate from one abnormal cell to more than 109 cells (the total number of cells ~1 cm in diameter in a tumor) if suitable conditions are available 20. Tumor cells will modify their metabolism to guarantee survival, overpower host immune attack, and maintain the proliferative capacity to induce their lethal effects and sustain survival 21. Cancer cells undergo physiological adaptations to preserve their survival under many stressful conditions, such as hypoxia and food hunger in order to fulfill their massive growth requirements. Such metabolic modifications generate abnormal metabolic events when compared to normal cells. This reprogrammed metabolism is seen as a cancer signature, as many metabolic modifications are predominant in several other types of cancers 22. Similar to normal cells, cancer cells also have to produce ATP to maintain both daughter cells formed through division, rely on metabolic intermediates or biosynthesis by-products and, most critically, to compete with the oxidizing effects to mitigate the impact of reactive oxygen species (ROS). These altered metabolic and bioenergetic mechanisms, significantly elevated biosynthesis and redox equilibrium, are crucial to cancer progression 23. Therefore, proliferating cells need to obtain high amounts of lipids, nucleotides, and amino acids. Through using by-products and derivatives of the TCA (tricarboxylic acid) cycle, cells can generate this biomass 24. It would appear that fulfilling all these requirements would require a significant boost in glucose uptake in tumors. The high glucose consumption in many, but not all, tumors have been verified by PET (positron emission tomography) imaging and glucose consumption rates beyond the levels that can be easily explained by energy or metabolite requirements 25. Moreover, the utilization of glutamine meets a symmetrical pattern of excessive consumption 26. It is believed that cancer metabolism could be described as upregulation of the metabolism of both glucose and glutamine for the production of energy.

2.1. Glucose

Glucose is the principal source of cellular energy and in the presence of oxygen, it is metabolized to pyruvate through glycolysis, which is transported to the mitochondria, where it is oxidatively metabolized into CO2 in the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation via electron transport chain (ETC) to produce high amounts of energy (for each molecule of glucose about 32 to 34 molecules of ATP are produced) 27. Cells may also undergo anaerobic glycolysis without oxygen, i.e., fermentation, diverting the resulting pyruvate molecules towards lactate production which is less effective in ATP production than the TCA cycle coupled with oxidative phosphorylation. Similarly, cancer cells primarily metabolize glucose, but in contrast to normal cells and in spite of the presence of oxygen, glycolysis produces lactate leading to the generation of two ATP per molecule of glucose. Consequently, cancer cells need a high glucose utilization efficiency so as to fulfill their energy and anabolic requirements, Otto Heinrich Warburg in 1920 found that even in ample oxygen, glycolysis was improved in cancer cells. However, glycolysis was commonly known to increase under anaerobic conditions 28. Despite deficiency in oxygen, increased glycolysis in cancer cells seemed to be a new phenomenon and was referred to as aerobic glycolysis or the “Warburg effect” 29. Consequently, the high quantity of glucose catabolism into lactate has been the most widespread metabolic phenotype detected in cancer cells, contributing to the deposition of lactate by-products within the tumor’s microenvironment 20. Currently, it is obvious that cancer cells experience aerobic glycolysis due to oncogene stimulation, tumor suppressor genes inhibition, and activation of phosphatidylinositol 3-kinase (PI3K) pathway, and that one benefit of high glycolytic frequencies is the availability of anabolic pathway substrates 30. The expression of glucose transporters in tumor cells is deregulated by some oncogenes (such as Myc oncogene), resulting in over-expression of these transporters, especially GLUT1 and GLUT3 31. The idea that cancer cells utilize glucose as a fuel is explained as follows; glucose begins to be processed in the cytosol, and is converted to glucose-6-phosphate (G6P) by Hexokinase (HK). Glucose-6-phosphate (G6P) is the splitting point from glycolysis to the pentose phosphate pathway oxidative branch (PPP) that produces the ribose group needed for nucleotide synthesis (RNA and DNA synthesis). This pathway is important in order to enable cancer cells to fulfill their anabolic demands and survive oxidative and nutritional stress 32. In this pathway, glucose-6-phosphate (G6P) is broken up into three-carbon compounds, 3-phosphoglyceraldehyde, which is the main point for the non-essential amino acid serine synthesis. Phosphoenolpyruvate (PEP) is also formed by glycolysis and end up producing two pyruvate molecules 20. The glycolytic enzyme pyruvate kinase enzyme (PK) is the final rate-limiting enzyme and is essential in pyruvate and ATP production. This enzyme has four isoforms (M1, M2, L, and R) which are expressed in different cell types. The PKM2 isoform is highly expressed in tumors thus shifting glucose metabolism towards anabolism through aerobic glycolysis and allowing the pyruvate product in the cytosol to be reduced to lactate by lactate dehydrogenase enzyme (LDH) 33,34,35. In cancer cells, lactate dehydrogenase enzyme (LDH) expression is upregulated which plays a crucial role in cancer characteristics 33.To sum up, cancer cells use catabolism of glucose as a main energy-generating mechanism by glycolysis and also from glucose, many biosynthetic compounds and NADPH molecules are produced. Glucose is the principal source of cellular energy and in the presence of oxygen, it is metabolized to pyruvate through glycolysis, which is transported to the mitochondria, where it is oxidatively metabolized into CO2 in the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation via electron transport chain (ETC) to produce high amounts of energy (for each molecule of glucose about 32 to 34 molecules of ATP are produced) 27. Cells may also undergo anaerobic glycolysis without oxygen, i.e., fermentation, diverting the resulting pyruvate molecules towards lactate production which is less effective in ATP production than the TCA cycle coupled with oxidative phosphorylation. Similarly, cancer cells primarily metabolize glucose, but in contrast to normal cells and in spite of the presence of oxygen, glycolysis produces lactate leading to the generation of two ATP per molecule of glucose. Consequently, cancer cells need a high glucose utilization efficiency so as to fulfill their energy and anabolic requirements, Otto Heinrich Warburg in 1920 found that even in ample oxygen, glycolysis was improved in cancer cells. However, glycolysis was commonly known to increase under anaerobic conditions 28. Despite deficiency in oxygen, increased glycolysis in cancer cells seemed to be a new phenomenon and was referred to as aerobic glycolysis or the “Warburg effect” 29. Consequently, the high quantity of glucose catabolism into lactate has been the most widespread metabolic phenotype detected in cancer cells, contributing to the deposition of lactate by-products within the tumor’s microenvironment 20. Currently, it is obvious that cancer cells experience aerobic glycolysis due to oncogene stimulation, tumor suppressor genes inhibition, and activation of phosphatidylinositol 3-kinase (PI3K) pathway, and that one benefit of high glycolytic frequencies is the availability of anabolic pathway substrates 30. The expression of glucose transporters in tumor cells is deregulated by some oncogenes (such as Myc oncogene), resulting in over-expression of these transporters, especially GLUT1 and GLUT3 31. The idea that cancer cells utilize glucose as a fuel is explained as follows; glucose begins to be processed in the cytosol, and is converted to glucose-6-phosphate (G6P) by Hexokinase (HK). Glucose-6-phosphate (G6P) is the splitting point from glycolysis to the pentose phosphate pathway oxidative branch (PPP) that produces the ribose group needed for nucleotide synthesis (RNA and DNA synthesis). This pathway is important in order to enable cancer cells to fulfill their anabolic demands and survive oxidative and nutritional stress 32. In this pathway, glucose-6-phosphate (G6P) is broken up into three-carbon compounds, 3-phosphoglyceraldehyde, which is the main point for the non-essential amino acid serine synthesis. Phosphoenolpyruvate (PEP) is also formed by glycolysis and end up producing two pyruvate molecules 20. The glycolytic enzyme pyruvate kinase enzyme (PK) is the final rate-limiting enzyme and is essential in pyruvate and ATP production. This enzyme has four isoforms (M1, M2, L, and R) which are expressed in different cell types. The PKM2 isoform is highly expressed in tumors thus shifting glucose metabolism towards anabolism through aerobic glycolysis and allowing the pyruvate product in the cytosol to be reduced to lactate by lactate dehydrogenase enzyme (LDH) 33,34,35. In cancer cells, lactate dehydrogenase enzyme (LDH) expression is upregulated which plays a crucial role in cancer characteristics 33.To sum up, cancer cells use catabolism of glucose as a main energy-generating mechanism by glycolysis and also from glucose, many biosynthetic compounds and NADPH molecules are produced.

2.2. Glutamine

The most common circulating amino acid in humans is glutamine. Glutamine is also the second most abundant nutrient after glucose in vitro cell culture environments, and its intake surpasses protein synthesis requirements 26. Via controlling mitochondrial reactive oxygen species (ROS) and proliferation, glutamine impacts the signaling pathways needed for cancer development, survival, and metabolism 36,37. Glutamine is taken up by proliferating cancer cells and converted to glutamate by various deamidation and transamination reactions, especially mitochondrial amidohydrolase glutaminase 38. Then, glutamate is transformed to alpha-ketoglutarate (α-KG) by glutamate dehydrogenase activity (or an aminotransferase) 39. Moreover, glutamine is used by rapidly developing tumor cells as a source of carbon for energy production as well as for the regenerating intermediates of the TCA cycle such as pyruvic acid, oxaloacetate, and α-KG to compensate for the continuous depletion of citrate exported from the mitochondria for lipid synthesis 37. (Figure 1) showing the metabolic alteration in cancer cell. The most common circulating amino acid in humans is glutamine. Glutamine is also the second most abundant nutrient after glucose in vitro cell culture environments, and its intake surpasses protein synthesis requirements 26. Via controlling mitochondrial reactive oxygen species (ROS) and proliferation, glutamine impacts the signaling pathways needed for cancer development, survival, and metabolism 36,37. Glutamine is taken up by proliferating cancer cells and converted to glutamate by various deamidation and transamination reactions, especially mitochondrial amidohydrolase glutaminase 38. Then, glutamate is transformed to alpha-ketoglutarate (α-KG) by glutamate dehydrogenase activity (or an aminotransferase) 39. Moreover, glutamine is used by rapidly developing tumor cells as a source of carbon for energy production as well as for the regenerating intermediates of the TCA cycle such as pyruvic acid, oxaloacetate, and α-KG to compensate for the continuous depletion of citrate exported from the mitochondria for lipid synthesis 37. (Figure 1) showing the metabolic alteration in cancer cell. A metabolic syndrome was described for the first time by Reavan in 1988, in which he suggested that it was an essential feature in developing Chronic Heart disease (CHD) and Diabetes Mellitus type II (DMTII), mostly through insulin resistance 40. Afterwards, established criteria for metabolic syndrome clinical identification have been emerged by NCEP-ATP III (the National Cholesterol Education Program/Adult Treatment Panel III) 41,42, WHO (the World Health Organization), IDF (the International Diabetes Federation) 43, and AACE (the American Association Clinical Endocrinologists) 44 (Shown in Table 1). According to NHANES III (the 3rd National Health and Nutrition Examination Survey) criteria, almost 47 million people have metabolic syndrome 45. Moreover, more than 2 in 10 cancers in the UK are thought to be related to metabolic syndrome 46. The risk of developing metabolic syndrome is increased with age, and it has been estimated that, in the age group of over 50 years, more than 40% in the United States and nearly 30% in Europe of this age group have metabolic syndrome 47,48. Recently, Esposito et al. using a meta-analysis, examined 38,940 patients with metabolic syndrome and cancer, and the study results showed that metabolic syndrome increases the risk of several cancers including colorectal, pancreas, and liver cancers. However, the reported results showed differences between genders. In men, the metabolic syndrome was strongly linked with both liver and colorectal cancers but weakly linked with bladder cancer. On the other hand in women, the metabolic syndrome was linked with endometrial, pancreas, breast (especially in postmenopausal women), colorectal, and ovary cancers 49. Table 1 summarizes various definition of metabolic syndrome. Insulin is considered the primary anabolic hormone and has an essential function in stimulating cell proliferation 51. In healthy individuals, the blood glucose level is tightly controlled by both insulin release and insulin-mediated glucose uptake in the tissues 52. On the other hand, when the response of the normal cells to insulin is weakened, a condition called insulin resistance is produced. As a result, the pancreas β-cells respond to this condition by increasing the secretion of insulin into the circulation, causing hyperinsulinemia (High insulin concentration in the blood in order to maintain a normal blood glucose level 53. Insulin resistance creates a favorable environment for neoplastic tissue survival and cancer cell development 54,55,56, this could be explained through the abnormally elevated levels of growth factors, ROS (Reactive Oxygen Species), adipokines, and proinflammatory cytokines that are associated with this condition. The primary mechanism for many features of metabolic syndrome is suggested to be insulin resistance or hyperinsulinemia. Studies have shown that chronic hyperinsulinemia is also associated with several cancer types such as colorectal, pancreatic, endometrial, and breast cancers 57. Hyperinsulinemia reduces the production of IGFBP-I and -II (Insulin-like growth factor binding protein) thus increasing IGF-I (Insulin-like growth factor) level in the blood, and promoting tumor development by changing the cellular environment 58. In addition, hyperinsulinemia inhibits the synthesis of SHBG Sex hormone-binding Globulin leading to increased free sex hormone levels thus promoting sex hormone-dependent cancers such as endometrial, breast and prostate cancers 58. Metabolic syndrome is also characterized by hyperglycemia 29, however, this does not mean that every diabetic patient has MetS since it is about three times more common than diabetes 59. The results of a study done by Flood et al. to investigate the relationship between insulin, fasting glucose, and colorectal adenomas recurrence risk, showed that the risk for colorectal recurrence is higher in patients with elevated insulin and glucose 60. A relationship between insulin resistance or hyperinsulinemia with different types of epithelial cancers has been shown by several population-based studies. Initial studies on prostate cancers showed a link with plasma IGF-I concentration 61. On the other hand, different studies have confirmed that both elevated IGF-I and insulin levels are associated with prostate cancer risk, prospectively 62,63,64. Moreover, a link has been shown between hyperinsulinemia and breast cancer risk (measured by fasting C-peptide concentration) mainly in postmenopausal breast cancer 65 and also with endometrial cancer risk independent of estradiol 66. The potential metabolic links between DM and cancer development are hyperinsulinemia, hyperglycemia, and chronic inflammation due to fat imbalanced metabolism.

4.1. Hyperinsulinemia

The role of insulin’s in carcinogenesis is mainly influenced by insulin receptor (IR), Insulin-like Growth Factor (IGF), and Insulin-like Growth Factor Receptor (IGF-R) 4. In diverse human malignancies, it was found that there is overexpression in the IR, the fetal isoform IR-A in particular, and in the IGF-R 67,68. Moreover, tumor cells can produce hybrid forms of insulin and IGF-1 receptors that can either be activated by insulin, IGF-1, and/or IGF-2 69. Insulin receptor (IR) is composed of two α-subunits and two β-subunits, expresses the activity of tyrosine kinase and is strongly activated by insulin, while both IGF-1 and IGF-2 possess weaker activation 70,71. The biochemical processes of insulin signaling proceed via autophosphorylation of IR itself and its direct substrate followed by activation of several pathways including the lipid kinase phosphor-inositide-phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of the rapamycin signaling pathway (mTOR) eventually leading to carcinogenesis via abnormal cells proliferation and inhibition of apoptosis 72. Increased mitogenesis was also observed in activated IRs in an insulin-resistant environment 73. Due to the structural similarity between IGF-R and IR (approximately 60% homology), insulin may also activate IGF-R 73. Activation of IR produces mainly metabolic effects, on the contrary activation of IGF-R by insulin produces mitogenic effects including cell proliferation, angiogenesis, and metastasis 67,74. Studies have verified that restriction of calorie consumption leads to reduced levels of insulin and IGF-1, complemented by declined insulin resistance and repressed mTOR pathway 75,76. Furthermore, hyperinsulinemia stimulates an increase of IGF-1 level through hepatic activation of growth hormone receptor (GHR), resulting in increased secretion of growth hormone (GH) which stimulates IGF-1 77. An elevated level of IGF-1 is considered a predisposing factor for premenopausal breast, prostate and colorectal carcinogenesis 78. Additionally, hyperinsulinemia also leads to a decreased level of IGF-binding protein 1,2, and 3 resulting in an increased level of bioavailable IGF-1 67,79. Elevated insulin level also minimizes liver production of sex-hormone-binding-protein (SHBG) and shortage of this protein increases the level of bioavailable estrogen or testosterone thus increasing the risk of hormone-dependent cancers 80. Likewise, hyperinsulinemia enhances the production of leptin (the mitogenic adipokine) by hypoxia-inducible factor-1α (HIF-1α). Although the mitogenic effect of leptin was believed to stimulate proliferation of esophagus, breast, and prostate cancer cells; it showed inhibitory activity on pancreatic cancer cells 81. The role of insulin’s in carcinogenesis is mainly influenced by insulin receptor (IR), Insulin-like Growth Factor (IGF), and Insulin-like Growth Factor Receptor (IGF-R) 4. In diverse human malignancies, it was found that there is overexpression in the IR, the fetal isoform IR-A in particular, and in the IGF-R 67,68. Moreover, tumor cells can produce hybrid forms of insulin and IGF-1 receptors that can either be activated by insulin, IGF-1, and/or IGF-2 69. Insulin receptor (IR) is composed of two α-subunits and two β-subunits, expresses the activity of tyrosine kinase and is strongly activated by insulin, while both IGF-1 and IGF-2 possess weaker activation 70,71. The biochemical processes of insulin signaling proceed via autophosphorylation of IR itself and its direct substrate followed by activation of several pathways including the lipid kinase phosphor-inositide-phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of the rapamycin signaling pathway (mTOR) eventually leading to carcinogenesis via abnormal cells proliferation and inhibition of apoptosis 72. Increased mitogenesis was also observed in activated IRs in an insulin-resistant environment 73. Due to the structural similarity between IGF-R and IR (approximately 60% homology), insulin may also activate IGF-R 73. Activation of IR produces mainly metabolic effects, on the contrary activation of IGF-R by insulin produces mitogenic effects including cell proliferation, angiogenesis, and metastasis 67,74. Studies have verified that restriction of calorie consumption leads to reduced levels of insulin and IGF-1, complemented by declined insulin resistance and repressed mTOR pathway 75,76. Furthermore, hyperinsulinemia stimulates an increase of IGF-1 level through hepatic activation of growth hormone receptor (GHR), resulting in increased secretion of growth hormone (GH) which stimulates IGF-1 77. An elevated level of IGF-1 is considered a predisposing factor for premenopausal breast, prostate and colorectal carcinogenesis 78. Additionally, hyperinsulinemia also leads to a decreased level of IGF-binding protein 1,2, and 3 resulting in an increased level of bioavailable IGF-1 67,79. Elevated insulin level also minimizes liver production of sex-hormone-binding-protein (SHBG) and shortage of this protein increases the level of bioavailable estrogen or testosterone thus increasing the risk of hormone-dependent cancers 80. Likewise, hyperinsulinemia enhances the production of leptin (the mitogenic adipokine) by hypoxia-inducible factor-1α (HIF-1α). Although the mitogenic effect of leptin was believed to stimulate proliferation of esophagus, breast, and prostate cancer cells; it showed inhibitory activity on pancreatic cancer cells 81.

4.2. Hyperglycemia

One of the notable characteristics of cancer cells is the increased uptake of glucose and enhanced glucose metabolism 82 to be able to grow and divide rapidly. Cancer cells possess altered metabolism via aerobic glycolysis, namely the “Warburg effect” 29. Hyperglycemia promotes tumor growth via proliferation, anti-apoptosis, and metastatic activity 83. The proliferative effect induced by hyperglycemia occurs as a result of overexpression of the following: glucose receptors (GLUT-1, GLUT-3) in tumor cells, protein kinase C (PKC-α), peroxisome proliferator-activated receptor (PPAR α and γ), and epithelial growth factor (EGF) 83. On the other hand, the anti-apoptotic activity of hyperglycemia is a consequence of the decreased level of prolyl hydroxylase (PDH) enzymes that eliminate the hypoxia-inducible factor α (HIF-α), thus leading to elevated HIF-α, which is a vital regulator of tumor cell survival in a hypoxic and anabolic environment. Additionally, hyperglycemia preserves cytochrome-c mediated apoptosis by elevated nicotinamide adenine dinucleotide phosphate (NADPH). Hyperglycemia also promotes metastasis and invasiveness due to several factors including epithelial to mesenchymal transition (ETM) process, oxidative stress via reduction of reactive oxygen species (ROS) and increased superoxide dismutase (SOD), and elevated expression of zinc transporters leading to enhanced zinc absorption which is involved in migration of cancer cells 84. Moreover, oxidative stress is a possible risk factor for carcinogenesis in diabetic people since it is the initial mechanism of insulin resistance; which is due to the inactivation of insulin receptors resulting from the overproduction of superoxide in the mitochondria 72.In addition, increased glucose levels affect the epigenetic regulation resulting in what is known as “hyperglycemic memory”; a condition that allows the activation of oncogenic pathways in hyperglycemia-exposed tumor cells, even after constant glucose level normalization 85. Glucose-induced constant expression of NF-κB p65-gene is the probable reason behind this mechanism 85. Interestingly Jee et al. suggested that fasting glucose level (FGL) > 125 mg/dL increases the risk of cancer incidence 86. On the contrary, a meta-analysis of major published trials clarified that the risk of cancer development was not reduced in type 2 diabetics who followed an intensified glycemic control 87. One of the notable characteristics of cancer cells is the increased uptake of glucose and enhanced glucose metabolism 82 to be able to grow and divide rapidly. Cancer cells possess altered metabolism via aerobic glycolysis, namely the “Warburg effect” 29. Hyperglycemia promotes tumor growth via proliferation, anti-apoptosis, and metastatic activity 83. The proliferative effect induced by hyperglycemia occurs as a result of overexpression of the following: glucose receptors (GLUT-1, GLUT-3) in tumor cells, protein kinase C (PKC-α), peroxisome proliferator-activated receptor (PPAR α and γ), and epithelial growth factor (EGF) 83. On the other hand, the anti-apoptotic activity of hyperglycemia is a consequence of the decreased level of prolyl hydroxylase (PDH) enzymes that eliminate the hypoxia-inducible factor α (HIF-α), thus leading to elevated HIF-α, which is a vital regulator of tumor cell survival in a hypoxic and anabolic environment. Additionally, hyperglycemia preserves cytochrome-c mediated apoptosis by elevated nicotinamide adenine dinucleotide phosphate (NADPH). Hyperglycemia also promotes metastasis and invasiveness due to several factors including epithelial to mesenchymal transition (ETM) process, oxidative stress via reduction of reactive oxygen species (ROS) and increased superoxide dismutase (SOD), and elevated expression of zinc transporters leading to enhanced zinc absorption which is involved in migration of cancer cells 84. Moreover, oxidative stress is a possible risk factor for carcinogenesis in diabetic people since it is the initial mechanism of insulin resistance; which is due to the inactivation of insulin receptors resulting from the overproduction of superoxide in the mitochondria 72. In addition, increased glucose levels affect the epigenetic regulation resulting in what is known as “hyperglycemic memory”; a condition that allows the activation of oncogenic pathways in hyperglycemia-exposed tumor cells, even after constant glucose level normalization 85. Glucose-induced constant expression of NF-κB p65-gene is the probable reason behind this mechanism 85. Interestingly Jee et al. suggested that fasting glucose level (FGL) > 125 mg/dL increases the risk of cancer incidence 86. On the contrary, a meta-analysis of major published trials clarified that the risk of cancer development was not reduced in type 2 diabetics who followed an intensified glycemic control 87.

4.3. Chronic Inflammation Due to Fat Imbalanced Metabolism

Obesity promotes tumorigenesis according to evolving studies 88,89 stressing that almost 80% of T2DM cases are associated with obesity and overweight 90. Numerous studies have also suggested that excess body adipose tissue is a risk factor for various types of cancers, including breast, endometrial, esophageal, pancreatic, and colorectal, cancers 88. The tumor-promoting activity of obesity can be probably explained by mechanisms such as alteration in sex hormones metabolism, changes in the levels of adipokines, chronic inflammation, and insulin resistance 80,88. Moreover, metabolic and mitogenic variations induced by excessive adipose tissue enhance the impact of hyperglycemia and hyperinsulinemia observed in T2DM. Figure 2 showed the metabolic relationship between diabetes and cancer. Obesity promotes tumorigenesis according to evolving studies 88,89 stressing that almost 80% of T2DM cases are associated with obesity and overweight 90. Numerous studies have also suggested that excess body adipose tissue is a risk factor for various types of cancers, including breast, endometrial, esophageal, pancreatic, and colorectal, cancers 88. The tumor-promoting activity of obesity can be probably explained by mechanisms such as alteration in sex hormones metabolism, changes in the levels of adipokines, chronic inflammation, and insulin resistance 80,88. Moreover, metabolic and mitogenic variations induced by excessive adipose tissue enhance the impact of hyperglycemia and hyperinsulinemia observed in T2DM. Figure 2 showed the metabolic relationship between diabetes and cancer.

4.4. Correlation between DM and Specific Cancer Examples

4.4.1. Liver Cancer

The most frequently observed malignant liver neoplasm in patients with DM is hepatocellular carcinoma (HCC) 91. The association between DM and a higher risk of HCC development was initially reported by Lawson in 1986 92, and was effectively supported by further researchers 91,93,94. These studies found that HCC is highly diagnosed in patients with non-alcoholic fatty liver disease (NAFLD), in obese patients with insulin resistance, and in T2DM patients 95,96. These disease conditions promote hepatic oncogenesis by several mechanisms, such as insulin resistance, modified adipokines pathophysiology, lipotoxicity and oxidative stress in the form of systemic inflammation. Furthermore, obesity accompanied by insulin resistance causes a decrease in adiponectin concentration and an increase in leptin, TNF-α, IL-6, and free fatty acids (FFA) concentrations, promoting growth, multiplication, and carcinogenesis in hepatic cells 96.Moreover, the liver is subjected to high insulin concentration as a result of portal circulation, thus leading to insulin-induced proliferation and suppression of apoptosis in hepatic cells 97.Additionally, HCC cells exhibit overexpression of both IGF-1 and insulin receptor substrate-1 (IRS-1), leading to the magnification of insulin effect. Furthermore, IRS-1 activates PI3K signaling and prevents apoptosis regulated by Transforming Growth Factor-β1 (TGF-β1), which is essential in hepatic cell carcinogenesis. Studies have also proposed that both T1DM and T2DM predispose to HCC, probably via hyperglycemia; in particular, a slightly stronger correlation was noted with T1DM than that with T2DM 98. On the other hand, data from various studies have suggested that T2DM with its simultaneous metabolic disorders activate oncogenesis in hepatic cells 99,100.

4.4.2. Prostate Cancer

Prostate cancer (PC) is the only described cancer in the literature associated with DM 101. Several studies reported the significant converse association between PC and DM which suggested a protective effect of DM against PC 101,102,103. Potential causes of this association involve a low testosterone level (probably due to high glucose level) and hypo-insulinemia observed in T1DM or T2DM in the long term. On the contrary, Li et al. suggested that DM is associated with an improved risk of advanced PC development 104.

4.4.1. Liver Cancer

The most frequently observed malignant liver neoplasm in patients with DM is hepatocellular carcinoma (HCC) 91. The association between DM and a higher risk of HCC development was initially reported by Lawson in 1986 92, and was effectively supported by further researchers 91,93,94. These studies found that HCC is highly diagnosed in patients with non-alcoholic fatty liver disease (NAFLD), in obese patients with insulin resistance, and in T2DM patients 95,96. These disease conditions promote hepatic oncogenesis by several mechanisms, such as insulin resistance, modified adipokines pathophysiology, lipotoxicity and oxidative stress in the form of systemic inflammation. Furthermore, obesity accompanied by insulin resistance causes a decrease in adiponectin concentration and an increase in leptin, TNF-α, IL-6, and free fatty acids (FFA) concentrations, promoting growth, multiplication, and carcinogenesis in hepatic cells 96.Moreover, the liver is subjected to high insulin concentration as a result of portal circulation, thus leading to insulin-induced proliferation and suppression of apoptosis in hepatic cells 97.Additionally, HCC cells exhibit overexpression of both IGF-1 and insulin receptor substrate-1 (IRS-1), leading to the magnification of insulin effect. Furthermore, IRS-1 activates PI3K signaling and prevents apoptosis regulated by Transforming Growth Factor-β1 (TGF-β1), which is essential in hepatic cell carcinogenesis. Studies have also proposed that both T1DM and T2DM predispose to HCC, probably via hyperglycemia; in particular, a slightly stronger correlation was noted with T1DM than that with T2DM 98. On the other hand, data from various studies have suggested that T2DM with its simultaneous metabolic disorders activate oncogenesis in hepatic cells 99,100. The most frequently observed malignant liver neoplasm in patients with DM is hepatocellular carcinoma (HCC) 91. The association between DM and a higher risk of HCC development was initially reported by Lawson in 1986 92, and was effectively supported by further researchers 91,93,94. These studies found that HCC is highly diagnosed in patients with non-alcoholic fatty liver disease (NAFLD), in obese patients with insulin resistance, and in T2DM patients 95,96. These disease conditions promote hepatic oncogenesis by several mechanisms, such as insulin resistance, modified adipokines pathophysiology, lipotoxicity and oxidative stress in the form of systemic inflammation. Furthermore, obesity accompanied by insulin resistance causes a decrease in adiponectin concentration and an increase in leptin, TNF-α, IL-6, and free fatty acids (FFA) concentrations, promoting growth, multiplication, and carcinogenesis in hepatic cells 96. Moreover, the liver is subjected to high insulin concentration as a result of portal circulation, thus leading to insulin-induced proliferation and suppression of apoptosis in hepatic cells 97. Additionally, HCC cells exhibit overexpression of both IGF-1 and insulin receptor substrate-1 (IRS-1), leading to the magnification of insulin effect. Furthermore, IRS-1 activates PI3K signaling and prevents apoptosis regulated by Transforming Growth Factor-β1 (TGF-β1), which is essential in hepatic cell carcinogenesis. Studies have also proposed that both T1DM and T2DM predispose to HCC, probably via hyperglycemia; in particular, a slightly stronger correlation was noted with T1DM than that with T2DM 98. On the other hand, data from various studies have suggested that T2DM with its simultaneous metabolic disorders activate oncogenesis in hepatic cells 99,100.

4.4.2. Prostate Cancer

Prostate cancer (PC) is the only described cancer in the literature associated with DM 101. Several studies reported the significant converse association between PC and DM which suggested a protective effect of DM against PC 101,102,103. Potential causes of this association involve a low testosterone level (probably due to high glucose level) and hypo-insulinemia observed in T1DM or T2DM in the long term. On the contrary, Li et al. suggested that DM is associated with an improved risk of advanced PC development 104. Prostate cancer (PC) is the only described cancer in the literature associated with DM 101. Several studies reported the significant converse association between PC and DM which suggested a protective effect of DM against PC 101,102,103. Potential causes of this association involve a low testosterone level (probably due to high glucose level) and hypo-insulinemia observed in T1DM or T2DM in the long term. On the contrary, Li et al. suggested that DM is associated with an improved risk of advanced PC development 104. Obesity is a major public health concern around the world, and it is now considered a crisis. It occurs as a result of changes in lifestyle (lack of physical activity, a high fat/calorie diet, a high carbohydrate diet) and is often related to lifestyle factors such as cigarette smoking and alcohol consumption. According to World Health Organization (WHO) over 1.9 billion people aged 18 and up were overweight in 2016. Over 650 million people were overweight (body mass index ≥ 25 kg/m2) or obese (body mass index ≥ 30 kg/m2) 105. Obesity and type 2 diabetes, “Diabesity is a new concept for diabetes that affects people who are obese” have become much more common across the world, which are commonly related to metabolic disorders and both are linked to a higher incidence and mortality rate which can accelerate cancer progression 106. Diabesity has been associated with the development of pancreatic cancer and its pathogenesis in many studies 107. In addition, it contributes to an increased risk of a number of different cancers, including breast, hematological and prostate cancer 108,109,110. Diabesity has been related to cancer progression through a number of mechanisms, including 1. insulin-like growth factor signaling, activation of the insulin/IGF signaling pathway has been presumed to lead to tumor initiation and/or progression just at the cellular level via tumor cell-specific mechanisms such as cell division activation and glucose metabolism 111 and epithelial-to-mesenchymal transition (EMT) 110 2. Insulin resistance and hyperinsulinemia are common in individuals with diabesity, C-peptide levels as indicators of insulin secretion have been tested in many studies to see whether hyperinsulinemia is related to cancer risk and mortality 112. A 37% increased risk of colorectal cancer has been linked to elevated C-peptide levels 113. According to the Physicians Health Report, obese men with increased C-peptide levels are likely to die from prostate cancer four times more than men with normal C-peptide levels 114. 3. Adipose tissue factors, adipose tissue is an important organ for the production of adipokines, inflammatory cytokines, and enzymes that are dysregulated in obesity and type 2 diabetes and potentially contribute to tumor growth and metastases 106,107,110. 4. Gut microbiome, Changes in the gut microbiota have been linked to an increased risk of some cancers by inducing inflammatory responses and leading to cancer proliferation 109. Recognizing the link between adipose tissue and tumors, the impact of obesity on immune cell function, and the effect of metabolic health on cancer progression will be crucial for enhancing current therapy responses and designing new therapies that address systemic metabolic. Various studies have indicated that cancer patients with diabetes have an inferior prognosis in comparison to non-diabetic patients. This could be explained since diabetes in cancer patients is a reason for higher infection rates, shorter remission periods, and higher mortality rates 55,115,116,117. Consequently, a variety of challenges face clinicians when treating cancer patients with diabetes because of the cardiac, neurologic, and renal complications associated with diabetic patients. Chemotherapeutic choices and treatment guidelines and, eventually, cancer outcomes could be affected due to the avoidance of using some of the best clinical agents with the best survival rates in cancer patients since these therapeutic agents may cause other disease complications 118.

6.1. Challenges Using Chemotherapeutic Agents

Cardiac, renal, and neuropathic complications usually develop in patients with poorly controlled diabetes and these complications can also be caused or exacerbated by many chemotherapeutic treatments. Anthracyclines, for example, may cause cardiotoxicity 119,120, and cisplatin could cause renal insufficiency. Consequently, the inability to use cisplatin in testicular cancer therapy decreases the overall response rates and survival 121. In addition, neurotoxicity, which is peripheral sensory neuropathy that occurs approximately in (40–50%) of diabetic patients, mainly in the feet, may also be caused by the use of cisplatin, vincristine, and paclitaxel; unfortunately, these side effects are usually permanent 122,123. Moreover, in order to achieve a successful cancer treatment, at least 85% of the chemotherapeutic dose should be given which necessitates careful monitoring of patients with cancer and diabetes before starting and during chemotherapy. Treatment of such patients must depend on the patient’s clinical picture since any alterations of the patient’s dose, time of administration, or changing between chemotherapeutic agents may affect the outcomes and lower the treatment response rate and also shorten patient’s survival rates 117,124,125. Cardiac, renal, and neuropathic complications usually develop in patients with poorly controlled diabetes and these complications can also be caused or exacerbated by many chemotherapeutic treatments. Anthracyclines, for example, may cause cardiotoxicity 119,120, and cisplatin could cause renal insufficiency. Consequently, the inability to use cisplatin in testicular cancer therapy decreases the overall response rates and survival 121. In addition, neurotoxicity, which is peripheral sensory neuropathy that occurs approximately in (40–50%) of diabetic patients, mainly in the feet, may also be caused by the use of cisplatin, vincristine, and paclitaxel; unfortunately, these side effects are usually permanent 122,123. Moreover, in order to achieve a successful cancer treatment, at least 85% of the chemotherapeutic dose should be given which necessitates careful monitoring of patients with cancer and diabetes before starting and during chemotherapy. Treatment of such patients must depend on the patient’s clinical picture since any alterations of the patient’s dose, time of administration, or changing between chemotherapeutic agents may affect the outcomes and lower the treatment response rate and also shorten patient’s survival rates 117,124,125.

6.2. Challenges Using Glucocorticoids

Several cancer treatment protocols regularly use glucocorticoids either in high doses for short-term therapy or in lower doses to alleviate nausea and vomiting that accompany treatment with chemotherapeutic agents. Therefore, before starting glucocorticoid therapy in any cancer patient, they should be tested for diabetes and also monitored closely after that, mostly because these patients have a high chance of being undiagnosed since up to a third of diabetic persons in the general public are undiagnosed 117. The mechanism of glucocorticoid action in raising blood glucose levels is by increased insulin resistance, glycogenolysis, gluconeogenesis, and decreased insulin production and secretion 126. Diagnosing cancer patients with diabetes during receiving glucocorticoid therapy is a common phenomenon as well. In addition, the most important factors for glucocorticoid-induced diabetes are increased age, obesity, a family history of diabetes or a history of gestational diabetes and treatment with high doses of steroids 127. Several cancer treatment protocols regularly use glucocorticoids either in high doses for short-term therapy or in lower doses to alleviate nausea and vomiting that accompany treatment with chemotherapeutic agents. Therefore, before starting glucocorticoid therapy in any cancer patient, they should be tested for diabetes and also monitored closely after that, mostly because these patients have a high chance of being undiagnosed since up to a third of diabetic persons in the general public are undiagnosed 117. The mechanism of glucocorticoid action in raising blood glucose levels is by increased insulin resistance, glycogenolysis, gluconeogenesis, and decreased insulin production and secretion 126. Diagnosing cancer patients with diabetes during receiving glucocorticoid therapy is a common phenomenon as well. In addition, the most important factors for glucocorticoid-induced diabetes are increased age, obesity, a family history of diabetes or a history of gestational diabetes and treatment with high doses of steroids 127.

6.3. Challenges of Using Cancer Treatments While on Glucose-Lowering Treatments

Glucose-lowering treatments may influence cancer treatments and ultimately impact cancer-specific mortality. A retrospective study was carried out by MD Anderson Cancer Centre in order to determine whether treatment with metformin had affected the pathologic complete response (pCR) rates in females with both diabetes and breast cancer on treatment with neoadjuvant chemotherapy 128. The study showed that the rate of pCR was 24% for women on metformin treatment, 8.0% for women on therapy other than metformin, and 16% for non-diabetic women; those results highlight that many diabetic patients manifest a weakened response rate to chemotherapy in comparison with non-diabetic patients. Furthermore, another two recently published studies affirmed similar results when metformin was used by diabetic patients with colorectal cancer 129, and also patients with advanced non-small-cell lung cancer undergoing first-line chemotherapy 130. Glucose-lowering treatments may influence cancer treatments and ultimately impact cancer-specific mortality. A retrospective study was carried out by MD Anderson Cancer Centre in order to determine whether treatment with metformin had affected the pathologic complete response (pCR) rates in females with both diabetes and breast cancer on treatment with neoadjuvant chemotherapy 128. The study showed that the rate of pCR was 24% for women on metformin treatment, 8.0% for women on therapy other than metformin, and 16% for non-diabetic women; those results highlight that many diabetic patients manifest a weakened response rate to chemotherapy in comparison with non-diabetic patients. Furthermore, another two recently published studies affirmed similar results when metformin was used by diabetic patients with colorectal cancer 129, and also patients with advanced non-small-cell lung cancer undergoing first-line chemotherapy 130. It is essential to state that glucose may be a potentially relevant cancer mediator taking into consideration the complexity of interactions between diabetes, diabetes treatments, and cancer. The Warburg hypothesis emphasizes how many types of cancer depend on glycolysis for energy, i.e., “glucose addiction” 29. One of the most effective diabetes management is to maintain improved control over blood glucose, thus reducing the risks of developing the complications associated with diabetes which leads to the minimization of morbidity and mortality rates. Therefore, regarding glucocorticoid therapy, rather than using a single bolus dose of steroids, giving steroids intravenous over 24 h or multiple doses during the day can better help control hyperglycemia in these patients. Diabetic patients treated with oral hypoglycemic medications may be kept on their medications while carefully monitoring their glucose levels. Nevertheless, in this case, these medications are usually inadequate for controlling hyperglycemia. On the other hand, diabetic patients who are on insulin therapy before starting the glucocorticoid therapy will usually need both basal and preprandial insulin administration and would need to increase their usual dose(s) of insulin two to three times. Moreover, in order to manage a patient’s induced or exacerbated hyperglycemia when using steroids, insulin is the preferred method in patients known with diabetes 126,127,131, and insulin doses are determined depending on the patient’s weight. A faster way to lower blood glucose levels is by intravenous insulin infusion which will also estimate the total required daily insulin dose for insulin naïve patients. However, many hospitals do not allow the use of intravenous insulin drips unless it is used in intensive care units due to the risk of hypoglycemia. Finally, insulin doses should be titrated daily and should also be tapered whenever glucocorticoid therapy is tapered in order to avoid hypoglycemia 126,127,131,132,133,134. In addition, clinicians often need a flexible approach to diabetes management in cancer patients because of the cyclical nature of chemotherapeutic agents, since platinum-based chemotherapy (e.g., cisplatin), mTOR kinase inhibitors (e.g., everolimus), and ABL kinase inhibitors (e.g., nilotinib) have all been connected to hyperglycemia. Unfortunately, there are few published articles related to this area. However, from the author’s experience, it is well known that diabetic patients with cancer need to be monitored frequently for hyperglycemic during therapy, especially in cases of advanced or incurable cancer patients undergoing palliative care 135.

8.1. Resveratrol

Resveratrol is a natural polyphenol that belongs to the class of stilbene 136. It is derived from various plant types and is presented in 34 families containing 100 species 137. In peanuts, soybeans, purple grapes and pomegranates, high resveratrol concentrations have been found 138. Resveratrol (3,5,40-trihydroxystilbene) is a stilbenoid and phytoalexin generated by a variety of plants as a result of injury or other pathogenic attacks 139. Resveratrol has historically been used to treat stomach pain, hepatitis, arthritis, urinary tract infections, and inflammatory and cardiovascular diseases 140. Several studies have recently reported the anticancer and antidiabetic effects of resveratrol.Resveratrol demonstrated antiproliferative and apoptotic effects on human cervical carcinoma cells by stimulating caspase-3 and caspase-9, impeding cell growth, inducing p53 expression, and upregulating the X-associated protein Bcl-2 141. It prevented the proliferation of colon cancer cells and induced cell apoptosis by suppressing the signaling pathway of AKT/STAT3 142. It enhanced paclitaxel’s apoptotic and oxidant effects by stimulating the TRPM2 channel in glioblastoma cells 143. Additionally, it inhibited pancreatic cancer cell metastasis by controlling the expressions of vimentin, CTA-2, IL-1β, TNF- α, and N-cadherin 144. Zhao et al. indicated that encapsulated resveratrol within peptide liposomes decreased free resveratrol’s toxicity and enhanced the physicochemical properties. It stimulated apoptosis in breast cancer by rising Bcl-2 activity, controlling p53 and Bax expression, and inducing the activation of caspase-3 145. A combination of thymoquinone and resveratrol was studied in both in vivo and in vitro models, and the findings demonstrated substantial cancer cell inhibition, angiogenesis suppression, and apoptosis elevation 146,147. A synergistic effect between resveratrol and doxorubicin against breast cancer cells was observed. In Ehrlich ascetic carcinoma cells carrying mice, combination therapy enhanced life span and decreased tumor volume 148.Resveratrol was examined in mice by analyzing postprandial glucose concentrations for its ability to inhibit α-glucosidase. The results showed that resveratrol delayed carbohydrate absorption, resulting in a reduced post-prandial blood glucose response 149. Several studies showed the antidiabetic effect of resveratrol 150. Resveratrol was revealed to enhance muscle and liver glucose absorption, decrease adipose tissue and liver inflammation, increase adaptive thermogenesis capability, and inhibit pancreatic insulin secretion 149. Quercetin and resveratrol were considered to have positive effects on diabetes. A study was conducted to investigate the combined antidiabetic action of quercetin and resveratrol in diabetic rats induced by streptozotocin. Elevated serum blood glucose, insulin levels, and dyslipidemia were significantly improved in diabetic rats by quercetin, resveratrol, and combination therapies. These compounds inhibited oxidative stress and tissue injury biomarkers substantially. Co-treatment of quercetin and resveratrol was useful against diabetes as it maintained the hepatic glucose metabolic enzymes activities and structure of pancreatic β-cells from the diabetes 151. Resveratrol is a natural polyphenol that belongs to the class of stilbene 136. It is derived from various plant types and is presented in 34 families containing 100 species 137. In peanuts, soybeans, purple grapes and pomegranates, high resveratrol concentrations have been found 138. Resveratrol (3,5,40-trihydroxystilbene) is a stilbenoid and phytoalexin generated by a variety of plants as a result of injury or other pathogenic attacks 139. Resveratrol has historically been used to treat stomach pain, hepatitis, arthritis, urinary tract infections, and inflammatory and cardiovascular diseases 140. Several studies have recently reported the anticancer and antidiabetic effects of resveratrol. Resveratrol demonstrated antiproliferative and apoptotic effects on human cervical carcinoma cells by stimulating caspase-3 and caspase-9, impeding cell growth, inducing p53 expression, and upregulating the X-associated protein Bcl-2 141. It prevented the proliferation of colon cancer cells and induced cell apoptosis by suppressing the signaling pathway of AKT/STAT3 142. It enhanced paclitaxel’s apoptotic and oxidant effects by stimulating the TRPM2 channel in glioblastoma cells 143. Additionally, it inhibited pancreatic cancer cell metastasis by controlling the expressions of vimentin, CTA-2, IL-1β, TNF- α, and N-cadherin 144. Zhao et al. indicated that encapsulated resveratrol within peptide liposomes decreased free resveratrol’s toxicity and enhanced the physicochemical properties. It stimulated apoptosis in breast cancer by rising Bcl-2 activity, controlling p53 and Bax expression, and inducing the activation of caspase-3 145. A combination of thymoquinone and resveratrol was studied in both in vivo and in vitro models, and the findings demonstrated substantial cancer cell inhibition, angiogenesis suppression, and apoptosis elevation 146,147. A synergistic effect between resveratrol and doxorubicin against breast cancer cells was observed. In Ehrlich ascetic carcinoma cells carrying mice, combination therapy enhanced life span and decreased tumor volume 148. Resveratrol was examined in mice by analyzing postprandial glucose concentrations for its ability to inhibit α-glucosidase. The results showed that resveratrol delayed carbohydrate absorption, resulting in a reduced post-prandial blood glucose response 149. Several studies showed the antidiabetic effect of resveratrol 150. Resveratrol was revealed to enhance muscle and liver glucose absorption, decrease adipose tissue and liver inflammation, increase adaptive thermogenesis capability, and inhibit pancreatic insulin secretion 149. Quercetin and resveratrol were considered to have positive effects on diabetes. A study was conducted to investigate the combined antidiabetic action of quercetin and resveratrol in diabetic rats induced by streptozotocin. Elevated serum blood glucose, insulin levels, and dyslipidemia were significantly improved in diabetic rats by quercetin, resveratrol, and combination therapies. These compounds inhibited oxidative stress and tissue injury biomarkers substantially. Co-treatment of quercetin and resveratrol was useful against diabetes as it maintained the hepatic glucose metabolic enzymes activities and structure of pancreatic β-cells from the diabetes 151.

8.2. Curcumin

One of three components of phenolic difrauloylmethane compounds known as curcuminoids is curcumin. It is a major active ingredient found in Curcuma longa dried rhizomes (family: Zingiberaceae), generally referred to as turmeric 152,153,154. Curcumin has several pharmacological properties such as anticancer, anti-diabetic, antioxidant, antiviral, antibacterial, anti-inflammatory, and wound-healing ability 152,154,155,156,157. Curcumin has been recognized as an anticancer agent via various mechanisms of action, including cancer cell apoptosis activation, cancer cell metastasis suppression, and cancer cell growth inhibition 155,158,159,160. Curcumin has been identified in several signaling pathways such as activation of apoptotic ligand-inducing tumor-necrosis-factor-related apoptosis (TRAIL) pathways in HT-29 and HCT-116 colon cancer cells by upregulating death receptor factor 5 161. In HT-29 colon cancer, curcumin began Fas-mediated apoptotic pathway through caspase 8 activation 162. Bax expression was upregulated and Bcl-2 was inhibited via phosphorylation at Ser15 and p53 activation in HT-29 colon adenocarcinoma cells 163, and HCT-116 155. The anti-cancer effect of curcumin on osteosarcoma was reported by inhibition of MG-63 cell proliferation and migration and inactivation of JAK/STAT signal 164. Curcumin was also useful against prostate cancer as it interfered with nuclear factor κ (NFκB), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinase (MAPK) 165.A study revealed that 14 days treatment of human adipocytes with turmeric ethanol extract, containing curcumin, demethoxycurcumin, bisdemethoxycurcumin and ar-turmerone, led to improved adipocyte differentiation substantially in a dose-dependent manner, increase glucose elevation levels and enhance the activity of human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding 166. Furthermore, treatment of 3T3-L1 adipocytes with curcumin decreased glucose uptake, leptin levels, NF-kB p65 nuclear fraction, phospho-JNK1/2, phospho-IRS-1(S), MMP-2, MMP-9 and VEGF protein. However, it elevated insulin sensitivity, adiponectin levels, and IRS-2 protein 166.Curcumin supplementation greatly stopped the progression and disruption of the renal lesion. It decreased the levels of urinary enzymes (acid phosphatase, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)). Additionally, it decreased lactate dehydrogenase and renal glucose-6-phosphatase and increased ATPase activity 167. The co-administration of curcumin and metformin reduced JAK/STAT signalling pathway expression substantially to suppress myocardial degeneration and diminish lipid peroxidation levels, IL-6, creatine kinase-MB (CK-MB), troponin I, and tumor growth factor-β1 (TGF-β1) 168. One of three components of phenolic difrauloylmethane compounds known as curcuminoids is curcumin. It is a major active ingredient found in Curcuma longa dried rhizomes (family: Zingiberaceae), generally referred to as turmeric 152,153,154. Curcumin has several pharmacological properties such as anticancer, anti-diabetic, antioxidant, antiviral, antibacterial, anti-inflammatory, and wound-healing ability 152,154,155,156,157. Curcumin has been recognized as an anticancer agent via various mechanisms of action, including cancer cell apoptosis activation, cancer cell metastasis suppression, and cancer cell growth inhibition 155,158,159,160. Curcumin has been identified in several signaling pathways such as activation of apoptotic ligand-inducing tumor-necrosis-factor-related apoptosis (TRAIL) pathways in HT-29 and HCT-116 colon cancer cells by upregulating death receptor factor 5 161. In HT-29 colon cancer, curcumin began Fas-mediated apoptotic pathway through caspase 8 activation 162. Bax expression was upregulated and Bcl-2 was inhibited via phosphorylation at Ser15 and p53 activation in HT-29 colon adenocarcinoma cells 163, and HCT-116 155. The anti-cancer effect of curcumin on osteosarcoma was reported by inhibition of MG-63 cell proliferation and migration and inactivation of JAK/STAT signal 164. Curcumin was also useful against prostate cancer as it interfered with nuclear factor κ (NFκB), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinase (MAPK) 165. A study revealed that 14 days treatment of human adipocytes with turmeric ethanol extract, containing curcumin, demethoxycurcumin, bisdemethoxycurcumin and ar-turmerone, led to improved adipocyte differentiation substantially in a dose-dependent manner, increase glucose elevation levels and enhance the activity of human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding 166. Furthermore, treatment of 3T3-L1 adipocytes with curcumin decreased glucose uptake, leptin levels, NF-kB p65 nuclear fraction, phospho-JNK1/2, phospho-IRS-1(S), MMP-2, MMP-9 and VEGF protein. However, it elevated insulin sensitivity, adiponectin levels, and IRS-2 protein 166. Curcumin supplementation greatly stopped the progression and disruption of the renal lesion. It decreased the levels of urinary enzymes (acid phosphatase, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)). Additionally, it decreased lactate dehydrogenase and renal glucose-6-phosphatase and increased ATPase activity 167. The co-administration of curcumin and metformin reduced JAK/STAT signalling pathway expression substantially to suppress myocardial degeneration and diminish lipid peroxidation levels, IL-6, creatine kinase-MB (CK-MB), troponin I, and tumor growth factor-β1 (TGF-β1) 168.

8.3. Thymoquinone

The major phytochemical bioactive constituent identified in volatile oil isolated from Nigella sativa (black cumin, black seed) is thymoquinone, which has been used in several countries as a traditional medicine 146,169,170. Thymoquinone has antihistaminic, immunomodulatory, antioxidant, antitumor, anti-inflammatory, and antimicrobial activities 170,171,172,173,174.Thymoquinone can be used as an anticancer agent as it can alter the regulation of cell cycle, growth factor, apoptosis, tumor-suppressor gene, protein kinase enzyme, transcription factors, survival signals, and phase I and II enzymes 170. Altering the progression of the cell cycle is an essential step in inhibiting the development and progression of cancer. Fatty acid-conjugated thymoquinone has a promising effect on apoptosis, cell proliferation, and signaling pathways 170. In the human mammary breast cancer epithelial cell line, MCF-7, thymoquinone induced cell arrest at various stages according to the concentration used (25 and 50 μM) in vivo 175. Furthermore, it was used to reduce serum TNF- α, IL-6, and iNOS enzyme production and improve histopathological outputs in Wistar rats with methotrexate-induced hepatorenal system injury 176. It played an important role in suppressing endothelial cell migration and tumor angiogenesis. In HCT 116 human colon cancer cells, thymoquinone significantly reduced the phosphorylation of EGFR to tyrosine-1173 residues and JAK2 in vitro 177. It has an antiproliferative effect, particularly when combined with doxorubicin and 5-fluorouracil, resulting in increased cytotoxicity in the xenograft mouse model of breast cancer 178. A study showed that thymoquinone activates apoptosis by reducing antiapoptotic protein expression 179.Thymoquinone has antidiabetic and antioxidant activities. It can reduce blood glucose level, triglycerides and cholesterol concentrations. On the other hand, it can improve the high-density lipoprotein, insulin sensitivity, and pancreatic β-cell regeneration resulting in substantial enhancement of the oral glucose tolerance test 180. Glycolysis and Kreb’s cycle pathways were used by thymoquinone to enhance glucose utilization while gluconeogenesis was used to decrease glucose production 181. Thymoquinone enhanced the antidiabetic effect of metformin 182. It can maintain the integrity of pancreatic β-cells by enhancing oxidative stress which subsequently raises the level of insulin 181. Nigella sativa consumption can reduce inflammatory and oxidative stress markers 183. Serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and malondialdehyde levels were significantly reduced by Nigella sativa intake, while total antioxidant ability and superoxide dismutase levels were significantly increased 183. The major phytochemical bioactive constituent identified in volatile oil isolated from Nigella sativa (black cumin, black seed) is thymoquinone, which has been used in several countries as a traditional medicine 146,169,170. Thymoquinone has antihistaminic, immunomodulatory, antioxidant, antitumor, anti-inflammatory, and antimicrobial activities 170,171,172,173,174. Thymoquinone can be used as an anticancer agent as it can alter the regulation of cell cycle, growth factor, apoptosis, tumor-suppressor gene, protein kinase enzyme, transcription factors, survival signals, and phase I and II enzymes 170. Altering the progression of the cell cycle is an essential step in inhibiting the development and progression of cancer. Fatty acid-conjugated thymoquinone has a promising effect on apoptosis, cell proliferation, and signaling pathways 170. In the human mammary breast cancer epithelial cell line, MCF-7, thymoquinone induced cell arrest at various stages according to the concentration used (25 and 50 μM) in vivo 175. Furthermore, it was used to reduce serum TNF- α, IL-6, and iNOS enzyme production and improve histopathological outputs in Wistar rats with methotrexate-induced hepatorenal system injury 176. It played an important role in suppressing endothelial cell migration and tumor angiogenesis. In HCT 116 human colon cancer cells, thymoquinone significantly reduced the phosphorylation of EGFR to tyrosine-1173 residues and JAK2 in vitro 177. It has an antiproliferative effect, particularly when combined with doxorubicin and 5-fluorouracil, resulting in increased cytotoxicity in the xenograft mouse model of breast cancer 178. A study showed that thymoquinone activates apoptosis by reducing antiapoptotic protein expression 179. Thymoquinone has antidiabetic and antioxidant activities. It can reduce blood glucose level, triglycerides and cholesterol concentrations. On the other hand, it can improve the high-density lipoprotein, insulin sensitivity, and pancreatic β-cell regeneration resulting in substantial enhancement of the oral glucose tolerance test 180. Glycolysis and Kreb’s cycle pathways were used by thymoquinone to enhance glucose utilization while gluconeogenesis was used to decrease glucose production 181. Thymoquinone enhanced the antidiabetic effect of metformin 182. It can maintain the integrity of pancreatic β-cells by enhancing oxidative stress which subsequently raises the level of insulin 181. Nigella sativa consumption can reduce inflammatory and oxidative stress markers 183. Serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and malondialdehyde levels were significantly reduced by Nigella sativa intake, while total antioxidant ability and superoxide dismutase levels were significantly increased 183.

8.4. EGCG (Epigallocatechin Gallate)

The natural polyphenol that belongs to the class of flavonols is epigallocatechin-3-gallate (EGCG) 184. Green tea (Camellia sinensis, Theaceae) 185 and cocoa products 186 are the major dietary sources of EGCG. Green tea was utilized in the past as a diuretic, astringent, stimulant, and to improve heart health in Indian and Chines medicine 187. EGCG has numerous medical benefits, including suppression of tumor growth, inhibition of irregular blood clot formation, and reduction of LDL cholesterol levels 188. EGCG is the most effective anti-inflammatory and anticancer agent among the various green tea catechin derivatives 189.EGCG can be utilized as an anticancer agent as it has antimetastasis, antiproliferative, and pro-apoptosis activities. The antimetastasis activity of EGCG was mediated by suppression of MMP-2 protein expression through modulation of the Src signaling pathway 190. The synergistic chemotherapeutic potential was demonstrated by the combination of EGCG with eugenol or amarogentin in the cervical cancer cell line 191. The antiproliferative effect of EGCG was proved by its capability to suppress cyclinD1 and improve LIMD1, RBSP3, and p16 cell-cycle inhibitors at the G1/S cell cycle level 192. Moreover, by reducing multi-drug resistance 1 signaling and stimulating the AKT/STAT3 pathway, EGCG was capable to alert cisplatin-resistant oral cancer CAR cell apoptosis and autophagy 193. The effect of EGCG on doxorubicin-induced cytotoxicity of oral keratinocytes and anticancer activity against oral cancer cells was reported. It reduced the doxorubicin cytotoxic effect without impairing its anticancer efficacy 194.EGCG has an antidiabetic effect. In a reversible and non-competitive way, EGCG inhibited α-glucosidase because of the complex formation between EGCG and α-glucosidase, where the hydrogen bonds played an important role, EGCG quenched α-glucosidase fluorescence. EGCG strongly affected the secondary structure and the microenvironment of α-glucosidase. Furthermore, EGCG increased the glucose uptake and stimulated GLUT4 translocation to the plasma membrane through PI3K/AKT signaling pathway in L6 skeletal muscle cells 195.EGCG also has an antiobesity effect. Green tea supplementation can help obese patients lose weight and lower their body mass index by several mechanisms, including inhibition of ghrelin secretion and adipogenesis, improvement of adiponectin levels, and reduction of nutrient absorption 196. The natural polyphenol that belongs to the class of flavonols is epigallocatechin-3-gallate (EGCG) 184. Green tea (Camellia sinensis, Theaceae) 185 and cocoa products 186 are the major dietary sources of EGCG. Green tea was utilized in the past as a diuretic, astringent, stimulant, and to improve heart health in Indian and Chines medicine 187. EGCG has numerous medical benefits, including suppression of tumor growth, inhibition of irregular blood clot formation, and reduction of LDL cholesterol levels 188. EGCG is the most effective anti-inflammatory and anticancer agent among the various green tea catechin derivatives 189. EGCG can be utilized as an anticancer agent as it has antimetastasis, antiproliferative, and pro-apoptosis activities. The antimetastasis activity of EGCG was mediated by suppression of MMP-2 protein expression through modulation of the Src signaling pathway 190. The synergistic chemotherapeutic potential was demonstrated by the combination of EGCG with eugenol or amarogentin in the cervical cancer cell line 191. The antiproliferative effect of EGCG was proved by its capability to suppress cyclinD1 and improve LIMD1, RBSP3, and p16 cell-cycle inhibitors at the G1/S cell cycle level 192. Moreover, by reducing multi-drug resistance 1 signaling and stimulating the AKT/STAT3 pathway, EGCG was capable to alert cisplatin-resistant oral cancer CAR cell apoptosis and autophagy 193. The effect of EGCG on doxorubicin-induced cytotoxicity of oral keratinocytes and anticancer activity against oral cancer cells was reported. It reduced the doxorubicin cytotoxic effect without impairing its anticancer efficacy 194. EGCG has an antidiabetic effect. In a reversible and non-competitive way, EGCG inhibited α-glucosidase because of the complex formation between EGCG and α-glucosidase, where the hydrogen bonds played an important role, EGCG quenched α-glucosidase fluorescence. EGCG strongly affected the secondary structure and the microenvironment of α-glucosidase. Furthermore, EGCG increased the glucose uptake and stimulated GLUT4 translocation to the plasma membrane through PI3K/AKT signaling pathway in L6 skeletal muscle cells 195. EGCG also has an antiobesity effect. Green tea supplementation can help obese patients lose weight and lower their body mass index by several mechanisms, including inhibition of ghrelin secretion and adipogenesis, improvement of adiponectin levels, and reduction of nutrient absorption 196.

8.5. Allicin

Allicin is a sulfenic acid thioester, or allyl thiosulfinate. It is predominantly present in garlic (Allium sativum) and belongs to the family Liliacerae 197. Allicin has various biological activities, including anticancer, antidiabetic, antimicrobial, and anti-inflammatory activity. Allicin substantially inhibited cholangiocarcinoma cell invasion and cell proliferation. It prohibited cell migration and prompted apoptosis via upregulation of SHP-1 and inhibition of the activation of STAT3 198. A study showed that allicin improved the X-ray radiotherapy sensitivity in colorectal cancer by inhibiting the signaling pathway of NF-κ 199. Furthermore, allicin demonstrated anti-tumor activity against HCMV-infected glioma cells through cytokine release downregulation, p53 activity stimulation, and radiotherapy sensitivity enhancement 200. Another study revealed allicin activity in stimulating apoptosis of cells and in suppressing ornithine decarboxylase which is a rate-limiting enzyme in neuroblastoma cell proliferation 201. By increasing cyclin D1 and reducing MMP-9 mRNA expression, allicin inhibited melanoma cell growth 202. Allicin also has synergistic anticancer activity against colorectal and lung carcinoma cells with 5-fluorouracil 203.Allicin has antidiabetic activities. It was helpful in the treatment of diabetic nephropathy 204. It enhanced insulin levels, reduced hyperglycemia, and prohibited changes in (GLUT4) and IRSs expression induced by diabetes 204. It also increased the expression of Nrf2 and decreased the expression of Keap1, HIF-1α, SBP, and VEGF 204. Treatment with allicin successfully decreased autoantibodies and anti-islet cell antibodies (ICA) for type 1 diabetes (IDDM). As a result, pancreatic tissues were restored and the decreased serum insulin level was greatly increased 205. Allicin is a sulfenic acid thioester, or allyl thiosulfinate. It is predominantly present in garlic (Allium sativum) and belongs to the family Liliacerae 197. Allicin has various biological activities, including anticancer, antidiabetic, antimicrobial, and anti-inflammatory activity. Allicin substantially inhibited cholangiocarcinoma cell invasion and cell proliferation. It prohibited cell migration and prompted apoptosis via upregulation of SHP-1 and inhibition of the activation of STAT3 198. A study showed that allicin improved the X-ray radiotherapy sensitivity in colorectal cancer by inhibiting the signaling pathway of NF-κ 199. Furthermore, allicin demonstrated anti-tumor activity against HCMV-infected glioma cells through cytokine release downregulation, p53 activity stimulation, and radiotherapy sensitivity enhancement 200. Another study revealed allicin activity in stimulating apoptosis of cells and in suppressing ornithine decarboxylase which is a rate-limiting enzyme in neuroblastoma cell proliferation 201. By increasing cyclin D1 and reducing MMP-9 mRNA expression, allicin inhibited melanoma cell growth 202. Allicin also has synergistic anticancer activity against colorectal and lung carcinoma cells with 5-fluorouracil 203. Allicin has antidiabetic activities. It was helpful in the treatment of diabetic nephropathy 204. It enhanced insulin levels, reduced hyperglycemia, and prohibited changes in (GLUT4) and IRSs expression induced by diabetes 204. It also increased the expression of Nrf2 and decreased the expression of Keap1, HIF-1α, SBP, and VEGF 204. Treatment with allicin successfully decreased autoantibodies and anti-islet cell antibodies (ICA) for type 1 diabetes (IDDM). As a result, pancreatic tissues were restored and the decreased serum insulin level was greatly increased 205.

8.6. Emodin

Emodin is most widely isolated from the Rheum palmatum (Chinese rhubarb, family: Polygonaceae) roots and rhizomes. It is also existed in Polygonum multiflorum (Chinese knotweed), Polygonum cuspidatum (Asian knotweed), Cassia obtusifolia (Chinese senna, family: Fabaceae), Aloe vera (family: Asphodelaceae), Aspergillus wentii, and Aspergillus ochraceus 206,207,208,209. Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural derivative of anthraquinone 210. It has different Pharmacological activities, including antitumor, antimetastatic, antiproliferative, antidiabetic, antiviral, antibacterial, anti-inflammatory, and immunosuppressive activity 211,212,213,214. Emodin’s molecular mechanisms are apoptosis, cell cycle arrest, and expression promotion of the detoxification enzymes hypoxia-inducible factor 1α, glutathione phase I and II, and glutathione S-transferase P,N-acetyltransferase. Emodin can also inhibit angiogenesis, invasion, migration, and formation of chemical-induced carcinogen-DNA adducts, HER2/neu, CKII kinase, and p34cdc2 kinase human cancer cells 215. Tumor-associated angiogenesis was inhibited via the reduction of ERK phosphorylation.Emodin has an important role in the treatment of diabetic nephropathy. It can reduce hyperglycaemia and stimulate cell proliferation and fibronectin expression by preventing cellular FLICE-inhibitory protein (cFLIP) and p38MAPK pathway. Additionally, it has a PPARγ-activating effect. It improved the symptoms of diabetic animals through PPARγ pathway regulation. Furthermore, glycolysis was improved by emodin through the AMPK signalling pathway 216. Emodin is most widely isolated from the Rheum palmatum (Chinese rhubarb, family: Polygonaceae) roots and rhizomes. It is also existed in Polygonum multiflorum (Chinese knotweed), Polygonum cuspidatum (Asian knotweed), Cassia obtusifolia (Chinese senna, family: Fabaceae), Aloe vera (family: Asphodelaceae), Aspergillus wentii, and Aspergillus ochraceus 206,207,208,209. Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural derivative of anthraquinone 210. It has different Pharmacological activities, including antitumor, antimetastatic, antiproliferative, antidiabetic, antiviral, antibacterial, anti-inflammatory, and immunosuppressive activity 211,212,213,214. Emodin’s molecular mechanisms are apoptosis, cell cycle arrest, and expression promotion of the detoxification enzymes hypoxia-inducible factor 1α, glutathione phase I and II, and glutathione S-transferase P,N-acetyltransferase. Emodin can also inhibit angiogenesis, invasion, migration, and formation of chemical-induced carcinogen-DNA adducts, HER2/neu, CKII kinase, and p34cdc2 kinase human cancer cells 215. Tumor-associated angiogenesis was inhibited via the reduction of ERK phosphorylation. Emodin has an important role in the treatment of diabetic nephropathy. It can reduce hyperglycaemia and stimulate cell proliferation and fibronectin expression by preventing cellular FLICE-inhibitory protein (cFLIP) and p38MAPK pathway. Additionally, it has a PPARγ-activating effect. It improved the symptoms of diabetic animals through PPARγ pathway regulation. Furthermore, glycolysis was improved by emodin through the AMPK signalling pathway 216.

8.7. Genistein

Genistein 40,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one is an isoflavonoid derivative and it belongs to phytoestrogen classes. It exists in glycosylated or free forms in food (mainly legumes). It was firstly isolated from Genista tinctoria. It was also found in lycine max (Soybean), soy-based foods, soy-based drinks, Lupin (Lupinus perennis), broad beans and chick peas. Genistein has pharmacological activities, including anticancer, antidiabetic, antiosteoporetic, and estrogenic activity 217,218. The mechanisms of genistein as anticancer agent include reducing proliferation, preventing angiogenesis and metastasis, and stimulating apoptosis 219,220. Genistein has a good inhibitory effect against various cancer cell lines, including melanoma (MML-1 and SK-MEL-2), breast carcinoma (MDA-MB-231 and T47D), pancreas carcinoma (BxPC-3 and PANC-1), colon carcinoma (HT29 and COLO201), glioblastoma (U87 and LN229), and lung carcinoma (A549 and NCI-H460) 221. Genistein was documented to inhibit cyclooxygenase-2 (COX-2) directly and indirectly by suppressing COX-2-stimulating factors such as activated protein-1 (AP-1) and Nf-κB. In pancreatic, colon, breast, and lung cancers, COX-2 overexpression was recognized and its inhibition was associated with decreased cancerous tumor growth in the esophagus and colon 217.A study stated that genistein has anti-inflammatory and antidiabetic functions, especially direct effects on the proliferation of β-cells and the secretion of insulin. Genistein improved glucose homeostasis 222. In β-cells, phytonutrient genistein easily stimulated cAMP signaling. It also improved the mass of islets in diabetic mice. CAMP generation genistein stimulation was eliminated in islets exposed to G15 unique GPR30 inhibitor or GPR30 deficient islets (GPR30−/−) mice 223. Genistein 40,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one is an isoflavonoid derivative and it belongs to phytoestrogen classes. It exists in glycosylated or free forms in food (mainly legumes). It was firstly isolated from Genista tinctoria. It was also found in lycine max (Soybean), soy-based foods, soy-based drinks, Lupin (Lupinus perennis), broad beans and chick peas. Genistein has pharmacological activities, including anticancer, antidiabetic, antiosteoporetic, and estrogenic activity 217,218. The mechanisms of genistein as anticancer agent include reducing proliferation, preventing angiogenesis and metastasis, and stimulating apoptosis 219,220. Genistein has a good inhibitory effect against various cancer cell lines, including melanoma (MML-1 and SK-MEL-2), breast carcinoma (MDA-MB-231 and T47D), pancreas carcinoma (BxPC-3 and PANC-1), colon carcinoma (HT29 and COLO201), glioblastoma (U87 and LN229), and lung carcinoma (A549 and NCI-H460) 221. Genistein was documented to inhibit cyclooxygenase-2 (COX-2) directly and indirectly by suppressing COX-2-stimulating factors such as activated protein-1 (AP-1) and Nf-κB. In pancreatic, colon, breast, and lung cancers, COX-2 overexpression was recognized and its inhibition was associated with decreased cancerous tumor growth in the esophagus and colon 217. A study stated that genistein has anti-inflammatory and antidiabetic functions, especially direct effects on the proliferation of β-cells and the secretion of insulin. Genistein improved glucose homeostasis 222. In β-cells, phytonutrient genistein easily stimulated cAMP signaling. It also improved the mass of islets in diabetic mice. CAMP generation genistein stimulation was eliminated in islets exposed to G15 unique GPR30 inhibitor or GPR30 deficient islets (GPR30−/−) mice 223.

8.8. Parthenolide

In the Asterceae family of medicinal plants, especially in Tanacetum parthenium (feverfew) 224, parthenolide is an essential naturally occurring metabolite 225. It can also be found in Tanacetum vulgare (tansy) and Tanacetum larvatum 226. Parthenolide was traditionally utilized to treat rheumatoid arthritis, fever, and migraine, while lately, it has been shown to have anticancer effects in various types of cancer, including bladder cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, leukemia, prostate cancer, and cholangiocarcinoma 227. Parthenolide’s anticancer mechanisms include DNA replication inhibition 216, STAT3 inhibition, apoptotic pathway stimulation 217, p.53 activation, and upregulation the production of reactive oxygen species (ROS) 228. A study reported that parthenolide directly affected malignant cells without affecting normal cells 229. Parthenolide was effective against distinct cholangiocarcinoma cell lines 230, because it induced apoptosis. Parthenolide inhibited breast cancer stem-like cells by stimulating oxidative stress and necrosis 231. Furthermore, the growth of transplanted glioblastoma cells was significantly inhibited by parthenolide 232. In pancreatic cancer cells, parthenolide can improve gemcitabine’s antiproliferative effects 233.Parthenolide can reduce inflammation and remodel the impaired insulin signaling pathway, allowing cubilin and albumin uptake to be expressed 234. During adipogenesis, adipogenic factors and lipid accumulation were reduced by parthenolide. In a dose-dependent manner, parthenolide inhibited adipogenic factors (PPARc and C/EBPa) and its target protein FABP4 production 235. The regulation of reactive oxygen species production by parthenolide was linked to the control of the Nrf2-(Keap1) pathway 235. In the Asterceae family of medicinal plants, especially in Tanacetum parthenium (feverfew) 224, parthenolide is an essential naturally occurring metabolite 225. It can also be found in Tanacetum vulgare (tansy) and Tanacetum larvatum 226. Parthenolide was traditionally utilized to treat rheumatoid arthritis, fever, and migraine, while lately, it has been shown to have anticancer effects in various types of cancer, including bladder cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, leukemia, prostate cancer, and cholangiocarcinoma 227. Parthenolide’s anticancer mechanisms include DNA replication inhibition 216, STAT3 inhibition, apoptotic pathway stimulation 217, p.53 activation, and upregulation the production of reactive oxygen species (ROS) 228. A study reported that parthenolide directly affected malignant cells without affecting normal cells 229. Parthenolide was effective against distinct cholangiocarcinoma cell lines 230, because it induced apoptosis. Parthenolide inhibited breast cancer stem-like cells by stimulating oxidative stress and necrosis 231. Furthermore, the growth of transplanted glioblastoma cells was significantly inhibited by parthenolide 232. In pancreatic cancer cells, parthenolide can improve gemcitabine’s antiproliferative effects 233. Parthenolide can reduce inflammation and remodel the impaired insulin signaling pathway, allowing cubilin and albumin uptake to be expressed 234. During adipogenesis, adipogenic factors and lipid accumulation were reduced by parthenolide. In a dose-dependent manner, parthenolide inhibited adipogenic factors (PPARc and C/EBPa) and its target protein FABP4 production 235. The regulation of reactive oxygen species production by parthenolide was linked to the control of the Nrf2-(Keap1) pathway 235.

8.9. Luteolin

Luteolin is a natural flavonoid abundantly present in many plant species. It is mainly found in vegetables and fruits, such as sweet bell peppers, carrots, onion leaves, broccoli, parsley, chrysanthemum flowers, and celery 236,237. It was isolated from Platycodon grandiflorum, Perilla frutescens, Apium graveolens, Cajanus cajan, Apium graveolens, Mentha spicata, and Sesbania grandifolra 238. Luteolin was utilized in the treatment of prostate, breast, pancreatic, skin, colon, oral, lung, ovarian, and kidney cancers 239. It has a potent cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and BT5-49 239. It obstructed cell proliferation and stimulated apoptosis of H460 and A549 cells 240,241,242. It inhibited metastasis, angiogenesis, and cell proliferation, and stimulated apoptosis through various mechanisms 243. The extrinsic and intrinsic apoptosis pathways were stimulated and the death receptor 5 expression was improved by luteolin 244. Stimulating JNK and obstructing translocation of NF-κB were mediated the cellular growth inhibition, G2 arrest, and apoptotic cell death induction 245. Furthermore, luteolin inhibited cancer cell proliferation by angiogenesis inhibition via blocking VEGF receptor stimulation and its downstream molecule PI3K/Akt and PI3K/p70S6 kinase pathways 246.Colon cancer and diabetes are the primary cause of death worldwide 247. Various luteolin signaling pathways, including SOD, p53, eNOS, Wnt, iNOS, MMP9, and the cyclin-CDK pathway, are used to treat cancer/diabetes 247. Since chronic hyperglycemia produces an intracellular level of reactive oxygen species, luteolin has anti-diabetic activity due to its antioxidant properties 247. Moreover, luteolin can regulate diabetes through mammalian targets of rapamycin (mTOR), cytokine, AMPK, and p53 247. Luteolin is a natural flavonoid abundantly present in many plant species. It is mainly found in vegetables and fruits, such as sweet bell peppers, carrots, onion leaves, broccoli, parsley, chrysanthemum flowers, and celery 236,237. It was isolated from Platycodon grandiflorum, Perilla frutescens, Apium graveolens, Cajanus cajan, Apium graveolens, Mentha spicata, and Sesbania grandifolra 238. Luteolin was utilized in the treatment of prostate, breast, pancreatic, skin, colon, oral, lung, ovarian, and kidney cancers 239. It has a potent cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and BT5-49 239. It obstructed cell proliferation and stimulated apoptosis of H460 and A549 cells 240,241,242. It inhibited metastasis, angiogenesis, and cell proliferation, and stimulated apoptosis through various mechanisms 243. The extrinsic and intrinsic apoptosis pathways were stimulated and the death receptor 5 expression was improved by luteolin 244. Stimulating JNK and obstructing translocation of NF-κB were mediated the cellular growth inhibition, G2 arrest, and apoptotic cell death induction 245. Furthermore, luteolin inhibited cancer cell proliferation by angiogenesis inhibition via blocking VEGF receptor stimulation and its downstream molecule PI3K/Akt and PI3K/p70S6 kinase pathways 246. Colon cancer and diabetes are the primary cause of death worldwide 247. Various luteolin signaling pathways, including SOD, p53, eNOS, Wnt, iNOS, MMP9, and the cyclin-CDK pathway, are used to treat cancer/diabetes 247. Since chronic hyperglycemia produces an intracellular level of reactive oxygen species, luteolin has anti-diabetic activity due to its antioxidant properties 247. Moreover, luteolin can regulate diabetes through mammalian targets of rapamycin (mTOR), cytokine, AMPK, and p53 247.

8.10. Quercetin

Quercetin is a polyphenolic flavonoid found in apples, berries, broccoli, onions, broccoli, green tea, red tea 248, Aesculus hippocastanum, Ginkgo biloba, and Hypericum perforatum 249. The biological activities of quercetin are anticancer, antidiabetic, antiobesity, neuroprotective, antimicrobial, antiviral, hepatoprotective, and anti-inflammatory activity 250. Quercetin stimulated apoptosis and inhibited cellular growth through the reduction of epidermal growth factor receptor (EGFR) expression 251. It induced apoptosis by directly upregulating caspase-3 and-9 and proapoptotic Bcl-2 family members, but it also induced apoptosis by directly downregulating antiapoptotic Bcl-xL 252. Moreover, it possessed a cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and MCF-7 via apoptosis activation along with G1 phase arrest 253,254. Quercetin improved the chemosensitivity of breast cancer cells to doxorubicin by obstructing proliferation and invasion of cells, leading to apoptosis activation 255. It also has good cytotoxic effects against human lung carcinoma A549 cells as it can inhibit cell invasion and migration, stimulate apoptosis, and decrease the number of tumor cells 256. A study showed that 16 weeks of administration of quercetin at a concentration of 200 and 400 mg/kg can decrease the number and the tumor size of papillomas in skin tumors prompted by croton oil in Swiss albino mice 257.Quercetin can decrease serum glucose level through several mechanisms, including antioxidant action, modulating hepatic gene expressions, obstructing α-glucosidase activity in vitro, and improving insulin action along with skeletal muscle mitochondrial biogenesis enhancement 258. It was utilized to reduce blood glucose and urine sugar levels, and increase plasma insulin and hemoglobin levels 259. Quercetin was found to be an effective PPAR-γ inhibitor 259. Quercetin is a polyphenolic flavonoid found in apples, berries, broccoli, onions, broccoli, green tea, red tea 248, Aesculus hippocastanum, Ginkgo biloba, and Hypericum perforatum 249. The biological activities of quercetin are anticancer, antidiabetic, antiobesity, neuroprotective, antimicrobial, antiviral, hepatoprotective, and anti-inflammatory activity 250. Quercetin stimulated apoptosis and inhibited cellular growth through the reduction of epidermal growth factor receptor (EGFR) expression 251. It induced apoptosis by directly upregulating caspase-3 and-9 and proapoptotic Bcl-2 family members, but it also induced apoptosis by directly downregulating antiapoptotic Bcl-xL 252. Moreover, it possessed a cytotoxic effect against different breast cancer cell lines, including MDA-MB-231 and MCF-7 via apoptosis activation along with G1 phase arrest 253,254. Quercetin improved the chemosensitivity of breast cancer cells to doxorubicin by obstructing proliferation and invasion of cells, leading to apoptosis activation 255. It also has good cytotoxic effects against human lung carcinoma A549 cells as it can inhibit cell invasion and migration, stimulate apoptosis, and decrease the number of tumor cells 256. A study showed that 16 weeks of administration of quercetin at a concentration of 200 and 400 mg/kg can decrease the number and the tumor size of papillomas in skin tumors prompted by croton oil in Swiss albino mice 257. Quercetin can decrease serum glucose level through several mechanisms, including antioxidant action, modulating hepatic gene expressions, obstructing α-glucosidase activity in vitro, and improving insulin action along with skeletal muscle mitochondrial biogenesis enhancement 258. It was utilized to reduce blood glucose and urine sugar levels, and increase plasma insulin and hemoglobin levels 259. Quercetin was found to be an effective PPAR-γ inhibitor 259.

8.11. Berberine

Berberine isolated from Coptis japonica Makino, Coptis chinensis Franch, and Berberis aristata Sims is an essential isoquinoline alkaloid. It is found in barberry, goldenseal, tree turmeric, and oregon grape 260. It is a pharmacologically significant secondary metabolite as it can help in the treatment of cancer, diabetes, and obesity 260.Colorectal, lung, liver, ovarian, prostate and cervical cancers are all inhibited by berberine 260. Under illumination with a black light lamp (320,450 nm; 20 W), SGC803 gastric cancer cells combined with berberine (10 g/mL) showed a good inhibitory proliferation effect. Additionally, berberine combined with 5-ALA-photodynamic therapy inhibits MGC-803 gastric cancer cell proliferation, reduces survivin and Bcl2 expression, stimulates cell apoptosis, and upregulates p53 and Bax expression. These findings imply that berberine has the ability to be utilized in conjunction with photosensitizers 260. Activating apoptosis and autophagy, inhibiting cell proliferation, and altering protein expression are berberine-photodynamic therapy’s mechanisms in treating tumors 260. Furthermore, berberine was utilized against breast cancer as it improved JNK phosphorylation, activated caspase-3, reduced the mitochondrial membrane potential, decreased the expression of Bcl-2, and increased the release of cytochrome c and AIF 261.Berberine decreased blood glucose and the risk of metabolic syndrome, improved insulin sensitivity, stimulated weight loss, improved lipid metabolism, reduced the levels of hemoglobin A1C and triglyceride, increased the mRNA expression of adiponectin, and reduced leptin and resistin secretion 262. Reduction of body weight, body mass index, and waist circumference was revealed after the administration of 500 mg of berberine either two or three times a day for three months 262. Berberine isolated from Coptis japonica Makino, Coptis chinensis Franch, and Berberis aristata Sims is an essential isoquinoline alkaloid. It is found in barberry, goldenseal, tree turmeric, and oregon grape 260. It is a pharmacologically significant secondary metabolite as it can help in the treatment of cancer, diabetes, and obesity 260. Colorectal, lung, liver, ovarian, prostate and cervical cancers are all inhibited by berberine 260. Under illumination with a black light lamp (320,450 nm; 20 W), SGC803 gastric cancer cells combined with berberine (10 g/mL) showed a good inhibitory proliferation effect. Additionally, berberine combined with 5-ALA-photodynamic therapy inhibits MGC-803 gastric cancer cell proliferation, reduces survivin and Bcl2 expression, stimulates cell apoptosis, and upregulates p53 and Bax expression. These findings imply that berberine has the ability to be utilized in conjunction with photosensitizers 260. Activating apoptosis and autophagy, inhibiting cell proliferation, and altering protein expression are berberine-photodynamic therapy’s mechanisms in treating tumors 260. Furthermore, berberine was utilized against breast cancer as it improved JNK phosphorylation, activated caspase-3, reduced the mitochondrial membrane potential, decreased the expression of Bcl-2, and increased the release of cytochrome c and AIF 261. Berberine decreased blood glucose and the risk of metabolic syndrome, improved insulin sensitivity, stimulated weight loss, improved lipid metabolism, reduced the levels of hemoglobin A1C and triglyceride, increased the mRNA expression of adiponectin, and reduced leptin and resistin secretion 262. Reduction of body weight, body mass index, and waist circumference was revealed after the administration of 500 mg of berberine either two or three times a day for three months 262.

8.12. Phytosterols

Phytosterols are plant-derived lipid compounds that are similar to cholesterol but differ in their carbon side chains and the presence or absence of a double bond. They are divided into two categories which are sterols (unsaturated compounds) and stanols (saturated molecules) 263. Phytosterols are commonly found in plants or macro fungi and have a number of pharmacological activities, including anticancer, hypolipidaemic, anti-inflammatory, and antidiabetic activity 263.Phytosterols can be utilized to improve breast, ovary, liver, lung, prostate and stomach cancers. They have several suggested mechanisms, including inhibition of carcinogen production, angiogenesis, cancer cell growth, multiplication, invasion, and metastasis and induction of apoptosis and cell cycle arrest 264. Female SCID mice were fed specified diets supplemented with 2% phytosterols, 2% cholesterol, or a 0.2% cholic acid vehicle to evaluate the effects of phytosterols on breast cancer cell growth and metastasis 264. After 2 weeks, mice were injected with MDA-MB-231 cells into their inguinal mammary fat pads. Eight weeks after the dietary supplementation, mice given phytosterols had a 40% reduction in serum cholesterol levels 264. Tumor sizes were 33% lower in animals fed the phytosterol diet compared to those fed the cholesterol diet 264. Tumor cell metastasis to lymph nodes and lungs was 57% of the phytosterol-fed animals and 71% of the cholesterol-fed animals 264. Another study showed that β-sitosterol enriched diet decreased tumor size in ovariectomized athymic mice injected with MCF-7 cells by 32–42% 264.Phytosterols have been shown to substantially lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the blood, and rise the HDL-C/LDL-C and HDL-C/TC indexes 265. Ergosterol could be a promising hypoglycemic agent for the treatment of type 2 diabetes, with a mechanism of stimulating GLUT4 translocation and expression through the PI3K/Akt and PKC pathways 265. Ergosterol was utilized to improve insulin resistance and blood lipid indices, and decrease fasting blood glucose levels. Furthermore, the phosphorylation of Akt and PKC was improved in different tissues 265. Table 2 summarizes the anticancer and antidiabetic mechanisms for selected natural products that target both diseases. Phytosterols are plant-derived lipid compounds that are similar to cholesterol but differ in their carbon side chains and the presence or absence of a double bond. They are divided into two categories which are sterols (unsaturated compounds) and stanols (saturated molecules) 263. Phytosterols are commonly found in plants or macro fungi and have a number of pharmacological activities, including anticancer, hypolipidaemic, anti-inflammatory, and antidiabetic activity 263. Phytosterols can be utilized to improve breast, ovary, liver, lung, prostate and stomach cancers. They have several suggested mechanisms, including inhibition of carcinogen production, angiogenesis, cancer cell growth, multiplication, invasion, and metastasis and induction of apoptosis and cell cycle arrest 264. Female SCID mice were fed specified diets supplemented with 2% phytosterols, 2% cholesterol, or a 0.2% cholic acid vehicle to evaluate the effects of phytosterols on breast cancer cell growth and metastasis 264. After 2 weeks, mice were injected with MDA-MB-231 cells into their inguinal mammary fat pads. Eight weeks after the dietary supplementation, mice given phytosterols had a 40% reduction in serum cholesterol levels 264. Tumor sizes were 33% lower in animals fed the phytosterol diet compared to those fed the cholesterol diet 264. Tumor cell metastasis to lymph nodes and lungs was 57% of the phytosterol-fed animals and 71% of the cholesterol-fed animals 264. Another study showed that β-sitosterol enriched diet decreased tumor size in ovariectomized athymic mice injected with MCF-7 cells by 32–42% 264. Phytosterols have been shown to substantially lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the blood, and rise the HDL-C/LDL-C and HDL-C/TC indexes 265. Ergosterol could be a promising hypoglycemic agent for the treatment of type 2 diabetes, with a mechanism of stimulating GLUT4 translocation and expression through the PI3K/Akt and PKC pathways 265. Ergosterol was utilized to improve insulin resistance and blood lipid indices, and decrease fasting blood glucose levels. Furthermore, the phosphorylation of Akt and PKC was improved in different tissues 265. Table 2 summarizes the anticancer and antidiabetic mechanisms for selected natural products that target both diseases. Research and studies about the role of reactive oxygen species (ROS) and the effect of exogenous administration of antioxidants’ supplements in cancer are opposed with controversy and conflicting outcomes. On one hand, antioxidants are commonly used by cancer patients and healthy individuals as a cancer-fighting strategy 269,270,271. Clinical trials with antioxidants, on the other hand, have shown contradictory findings; some trials showed that antioxidants raised cancer risks 272,273,274,275. Klein A et al. conducted a study between 2004 and 2011 and found that prostate cancer risk for healthy men was markedly increased upon supplementation with 400 IU/day of vitamin E supplement 276, whereas VI Sayin et al. clarified that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E noticeably enhances human lung cancer cells proliferation and tumor progression in mice with B-RAF- and K-RAS-induced lung cancer via decreasing ROS, DNA damage, and p53 levels. Additionally, Volkan S. et al. showed that the antioxidants supplementation may accelerate early tumors or precancerous lesions growth in elevated-risk populations (like smokers and chronic obstructive pulmonary disease patients who receive NAC to reduce mucus production) because the somatic p53 mutations occur late in the tumor progression process 277. Another study by Clotilde W. et al. demonstrated that long-term supplementation of NAC and vitamin E stimulates K-RAS-induced lung cancer metastasis by decreasing free heme levels and stabilizing the pro-metastatic basic leucine zipper transcription factor 1 (BACH1). BACH1 stimulates glycolysis-dependent metastasis of mouse and human lung cancer cells by activating transcription of Hexokinase 2 and Gapdh and increasing glucose uptake, glycolysis rates, and lactate secretion 278. Moreover, Le Gal et al. studied the effect of antioxidants on malignant melanoma in a mouse model and showed that the administration of NAC and Trolox (the soluble vitamin E analog) expand lymph node metastases and cause increased glutathione-synthesis-dependent invasiveness 279. Indicating that active tumors preserve ROS levels within limits that stimulate proliferation without leading to cytotoxicity 280. Similar results of melanoma metastasis were found in a different mouse model (NOD-SCID Il2rg−/− (NSG) mice) when supplemented regularly with subcutaneous injection of NAC 281. Clinical trials involving the use of antioxidants combined with chemotherapy are summarized in Table 3. In conclusion, the supplementation of exogenous antioxidants may aid cancer cells to navigate the metastatic cascade and adopt adaptive steps to counteract the beneficial effect of antioxidant supplements. Nevertheless; additional clinical studies are required to confirm the generalizability of these remarks and to expand them to practical application especially with existing cancer patients. Cancer and diabetes represent global health challenges and the number of patients is contentiously increasing for both diseases. Hyperglycemia, hyperinsulinemia, and imbalanced fat metabolism in diabetic patients increase the altered metabolism in cancer cells. This metabolic link between cancer and diabetes complicates therapeutic protocols and reduces survival rates. Natural products with their diverse mechanisms of action can be used as adjuvant therapy to enhance conventional treatments. These natural products act by targeting interconnected mechanisms between cancer and diabetes. Further research is needed to explore the potential use of natural products in combination therapies to treat cancer in diabetic patients. The authors are grateful to the Applied Science Private University, Amman, Jordan, for the full financial support granted to this research (Grant No. DRGS-2020-2021-4). Not applicable. Not applicable. The authors declare no conflict of interest. 611. Zimmet, P.; Alberti, K.G.; Magliano, D.J.; Bennett, P.H. Diabetes mellitus statistics on prevalence and mortality: Facts and fallacies. Nat. Rev. Endocrinol.2016, 12, 616–622. Google Scholar CrossRef 612. Asmat, U.; Abad, K.; Ismail, K. Diabetes mellitus and oxidative stress—A concise review. Saudi Pharm. J.2016, 24, 547–553. Google Scholar CrossRef Green Version 613. Giri, B.; Dey, S.; Das, T.; Sarkar, M.; Banerjee, J.; Dash, S.K. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed. Pharmacother.2018, 107, 306–328. Google Scholar CrossRef 614. Wojciechowska, J.; Krajewski, W.; Bolanowski, M.; Kręcicki, T.; Zatoński, T. Diabetes and cancer: A review of current knowledge. Exp. Clin. Endocrinol. Diabetes2016, 124, 263–275. Google Scholar CrossRef 615. Suh, S.; Kim, K.-W. Diabetes and cancer: Cancer should be screened in routine diabetes assessment. Diabetes Metab. J.2019, 43, 733. Google Scholar CrossRef 616. De Martel, C.; Georges, D.; Bray, F.; Ferlay, J.; Clifford, G.M. Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis. Lancet Glob. Health2020, 8, e180–e190. Google Scholar CrossRef Green Version 617. Cignarelli, A.; Genchi, V.A.; Caruso, I.; Natalicchio, A.; Perrini, S.; Laviola, L.; Giorgino, F. Diabetes and cancer: Pathophysiological fundamentals of a ‘dangerous affair’. Diabetes Res. Clin. Pract.2018, 143, 378–388. Google Scholar CrossRef 618. Lee, C.; An, D.; Park, J. Hyperglycemic memory in metabolism and cancer. Horm. Mol. Biol. Clin. Investig.2016, 26, 77–85. Google Scholar CrossRef 619. Ferroni, P.; Riondino, S.; Buonomo, O.; Palmirotta, R.; Guadagni, F.; Roselli, M. Type 2 diabetes and breast cancer: The interplay between impaired glucose metabolism and oxidant stress. Oxid. Med. Cell. Longev.2015, 2015, 183928. Google Scholar CrossRef 620. Srivastava, S.P.; Goodwin, J.E. Cancer biology and prevention in diabetes. Cells2020, 9, 1380. Google Scholar CrossRef 621. Sampayo, V.; Tofthagen, C. Hyperglycemia and Cancer: An algorithm to guide oncology nurses. Clin. J. Oncol. Nurs.2017, 21, 345–352. Google Scholar CrossRef 622. Ben, Q.; Xu, M.; Ning, X.; Liu, J.; Hong, S.; Huang, W.; Zhang, H.; Li, Z. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur. J. Cancer2011, 47, 1928–1937. Google Scholar CrossRef 623. Elena, J.W.; Steplowski, E.; Yu, K.; Hartge, P.; Tobias, G.S.; Brotzman, M.J.; Chanock, S.J.; Stolzenberg-Solomon, R.Z.; Arslan, A.A.; Bueno-de-Mesquita, H.B. Diabetes and risk of pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control2013, 24, 13–25. Google Scholar CrossRef 624. Villarreal-Garza, C.; Shaw-Dulin, R.; Lara-Medina, F.; Bacon, L.; Rivera, D.; Urzua, L.; Aguila, C.; Ramirez-Morales, R.; Santamaria, J.; Bargallo, E. Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. Exp. Diabetes Res.2012, 2012, 732027. Google Scholar CrossRef 625. Bjornsdottir, H.H.; Rawshani, A.; Rawshani, A.; Franzén, S.; Svensson, A.-M.; Sattar, N.; Gudbjörnsdottir, S. A national observation study of cancer incidence and mortality risks in type 2 diabetes compared to the background population over time. Sci. Rep.2020, 10, 1–12. Google Scholar CrossRef 626. Samuel, S.M.; Varghese, E.; Varghese, S.; Büsselberg, D. Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat. Rev.2018, 70, 98–111. Google Scholar CrossRef Green Version 627. Zeng, L.; Zielinska, H.; Arshad, A.; Shield, J.; Bahl, A.; Holly, J.; Perks, C. Hyperglycaemia-induced chemoresistance in breast cancer cells: Role of the estrogen receptor. Endocr. Relat. Cancer2016, 23, 125–134. Google Scholar CrossRef PubMed Green Version 628. Vigneri, P.; Frasca, F.; Sciacca, L.; Pandini, G.; Vigneri, R. Diabetes and cancer. Endocr. Relat. Cancer2009, 16, 1103–1123. Google Scholar CrossRef PubMed Green Version 629. Harding, J.L.; Andes, L.J.; Gregg, E.W.; Cheng, Y.J.; Weir, H.K.; Bullard, K.M.; Burrows, N.R.; Imperatore, G. Trends in cancer mortality among people with vs. without diabetes in the USA, 1988–2015. Diabetologia2020, 63, 75–84. Google Scholar CrossRef PubMed 630. Lunt, S.Y.; Vander Heiden, M.G. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol.2011, 27, 441–464. Google Scholar CrossRef Green Version 631. Villalba, M.; Rathore, M.G.; Lopez-Royuela, N.; Krzywinska, E.; Garaude, J.; Allende-Vega, N. From tumor cell metabolism to tumor immune escape. Int. J. Biochem. Cell Biol.2013, 45, 106–113. Google Scholar CrossRef Green Version 632. Pavlova, N.N.; Thompson, C.B. The emerging hallmarks of cancer metabolism. Cell Metab.2016, 23, 27–47. Google Scholar CrossRef Green Version 633. DeBerardinis, R.J.; Chandel, N.S. Fundamentals of cancer metabolism. Sci. Adv.2016, 2, e1600200. Google Scholar CrossRef Green Version 634. Danhier, P.; Bański, P.; Payen, V.L.; Grasso, D.; Ippolito, L.; Sonveaux, P.; Porporato, P.E. Cancer metabolism in space and time: Beyond the Warburg effect. Biochim. Biophys. Acta (BBA) Bioenerg.2017, 1858, 556–572. Google Scholar CrossRef 635. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell2011, 144, 646–674. Google Scholar CrossRef Green Version 636. Matés, J.M.; Campos-Sandoval, J.A.; de Los Santos-Jiménez, J.; Márquez, J. Dysregulation of glutaminase and glutamine synthetase in cancer. Cancer Lett.2019, 467, 29–39. Google Scholar CrossRef 637. Bose, S.; Le, A. Glucose Metabolism in Cancer. Adv. Exp. Med. Biol.2018, 1063, 3–12. Google Scholar PubMed 638. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol.1927, 8, 519–530. Google Scholar CrossRef PubMed Green Version 639. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science2009, 324, 1029–1033. Google Scholar CrossRef PubMed Green Version 640. Patra, K.C.; Wang, Q.; Bhaskar, P.T.; Miller, L.; Wang, Z.; Wheaton, W.; Chandel, N.; Laakso, M.; Muller, W.J.; Allen, E.L. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell2013, 24, 213–228. Google Scholar CrossRef PubMed Green Version 641. Hsieh, A.L.; Walton, Z.E.; Altman, B.J.; Stine, Z.E.; Dang, C.V. Seminars in Cell & Developmental Biology. In MYC and Metabolism on the Path to Cancer; Elsevier: Amsterdam, The Netherlands, 2015; pp. 11–21. Google Scholar 642. Fadaka, A.; Ajiboye, B.; Ojo, O.; Adewale, O.; Olayide, I.; Emuowhochere, R. Biology of glucose metabolization in cancer cells. J. Oncol. Sci.2017, 3, 45–51. Google Scholar CrossRef 643. Feng, Y.; Xiong, Y.; Qiao, T.; Li, X.; Jia, L.; Han, Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med.2018, 7, 6124–6136. Google Scholar CrossRef Green Version 644. Palsson-McDermott, E.M.; Curtis, A.M.; Goel, G.; Lauterbach, M.A.; Sheedy, F.J.; Gleeson, L.E.; van den Bosch, M.W.; Quinn, S.R.; Domingo-Fernandez, R.; Johnston, D.G. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab.2015, 21, 65–80. Google Scholar CrossRef Green Version 645. Seton-Rogers, S. Feed it forward. Nat. Rev. Cancer2011, 11, 461. Google Scholar CrossRef 646. Daye, D.; Wellen, K.E. Seminars in Cell & Developmental Biology. In Metabolic Reprogramming in Cancer: Unraveling the Role of Glutamine in Tumorigenesis; Elsevier: Amsterdam, The Netherlands, 2012; pp. 362–369. Google Scholar 647. Phan, L.M.; Yeung, S.-C.J.; Lee, M.-H. Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol. Med.2014, 11, 1. Google Scholar PubMed 648. Hensley, C.T.; Wasti, A.T.; DeBerardinis, R.J. Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J. Clin. Investig.2013, 123, 3678–3684. Google Scholar CrossRef Green Version 649. Deshmukh, A.; Deshpande, K.; Arfuso, F.; Newsholme, P.; Dharmarajan, A. Cancer stem cell metabolism: A potential target for cancer therapy. Mol. Cancer2016, 15, 1–10. Google Scholar CrossRef Green Version 650. Reaven, G.M. Role of insulin resistance in human disease. Diabetes1988, 37, 1595–1607. Google Scholar CrossRef PubMed 651. Alberti, K.; Eckel, R.H.; Grundy, S.M.; Zimmet, P.Z.; Cleeman, J.I.; Donato, K.A.; Fruchart, J.-C.; James, W.P.T.; Loria, C.M.; Smith, S.C., Jr. Harmonizing the metabolic syndrome: A joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation2009, 120, 1640–1645. Google Scholar 652. Lakka, H.-M.; Laaksonen, D.E.; Lakka, T.A.; Niskanen, L.K.; Kumpusalo, E.; Tuomilehto, J.; Salonen, J.T. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA2002, 288, 2709–2716. Google Scholar CrossRef 653. Alberti, K.G.M.M.; Zimmet, P.; Shaw, J. Metabolic syndrome—A new world-wide definition. A consensus statement from the international diabetes federation. Diabet. Med.2006, 23, 469–480. Google Scholar CrossRef 654. Ford, E.S. Insulin resistance syndrome: The public health challenge. Endocr. Pract.2003, 9, 23. Google Scholar CrossRef 655. Ford, E.S.; Giles, W.H.; Dietz, W.H. Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA2002, 287, 356–359. Google Scholar CrossRef PubMed 656. Nashar, K.; Egan, B.M. Relationship between chronic kidney disease and metabolic syndrome: Current perspectives. Diabetes Metab. Syndr. Obes. Targets Ther.2014, 7, 421. Google Scholar CrossRef Green Version 657. Cameron, A.J.; Shaw, J.E.; Zimmet, P.Z. The metabolic syndrome: Prevalence in worldwide populations. Endocrinol. Metab. Clin.2004, 33, 351–375. Google Scholar CrossRef 658. Ford, E.S.; Giles, W.H.; Mokdad, A.H. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care2004, 27, 2444–2449. Google Scholar CrossRef Green Version 659. Esposito, K.; Chiodini, P.; Colao, A.; Lenzi, A.; Giugliano, D. Metabolic syndrome and risk of cancer: A systematic review and meta-analysis. Diabetes Care2012, 35, 2402–2411. Google Scholar CrossRef Green Version 660. Alberti, K.G.M.; Zimmet, P.; Shaw, J. The metabolic syndrome—A new worldwide definition. Lancet2005, 366, 1059–1062. Google Scholar CrossRef 661. Duvnjak, L.; Duvnjak, M. The metabolic syndrome-an ongoing story. J. Physiol. Pharmacol.2009, 60 (Suppl. S7), 19–24. Google Scholar 662. Djiogue, S.; Nwabo Kamdje, A.H.; Vecchio, L.; Kipanyula, M.J.; Farahna, M.; Aldebasi, Y.; Seke Etet, P. Insulin resistance and cancer: The role of insulin and IGFs. Endocr. Relat. Cancer2013, 20, R1–R17. Google Scholar CrossRef Green Version 663. Cowey, S.; Hardy, R.W. The metabolic syndrome: A high-risk state for cancer? Am. J. Pathol.2006, 169, 1505–1522. Google Scholar CrossRef PubMed 664. Etet, P.F.S.; Vecchio, L.; Kamdje, A.H.N. Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: Any role for Notch, Wnt and Hh signaling pathways? Cell. Signal.2012, 24, 1433–1443. Google Scholar CrossRef 665. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat. Rev. Cancer2012, 12, 159–169. Google Scholar CrossRef 666. Sakurai, T.; Kudo, M. Signaling pathways governing tumor angiogenesis. Oncology2011, 81 (Suppl. S1), 24–29. Google Scholar CrossRef 667. Jee, S.H.; Kim, H.J.; Lee, J. Obesity, insulin resistance and cancer risk. Yonsei Med. J.2005, 46, 449. Google Scholar CrossRef Green Version 668. Calle, E.E.; Kaaks, R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer2004, 4, 579–591. Google Scholar CrossRef 669. Saklayen, M.G. The Global Epidemic of the Metabolic Syndrome. Curr. Hypertens. Rep.2018, 20, 12. Google Scholar CrossRef PubMed Green Version 670. Flood, A.; Mai, V.; Pfeiffer, R.; Kahle, L.; Remaley, A.T.; Lanza, E.; Schatzkin, A. Elevated serum concentrations of insulin and glucose increase risk of recurrent colorectal adenomas. Gastroenterology2007, 133, 1423–1429. Google Scholar CrossRef PubMed 671. Chan, J.M.; Stampfer, M.J.; Giovannucci, E.; Gann, P.H.; Ma, J.; Wilkinson, P.; Hennekens, C.H.; Pollak, M. Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study. Science1998, 279, 563–566. Google Scholar CrossRef 672. Giovannucci, E.; Rimm, E.B.; Liu, Y.; Willett, W.C. Height, predictors of C-peptide and cancer risk in men. Int. J. Epidemiol.2004, 33, 217–225. Google Scholar CrossRef 673. Harman, S.M.; Metter, E.J.; Blackman, M.R.; Landis, P.K.; Carter, H.B. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer. J. Clin. Endocrinol. Metab.2000, 85, 4258–4265. Google Scholar CrossRef 674. Kaaks, R.; Lukanova, A.; Rinaldi, S.; Biessy, C.; Söderberg, S.; Olsson, T.; Stenman, U.-H.; Riboli, E.; Hallmans, G.; Stattin, P. Interrelationships between plasma testosterone, SHBG, IGF-I, insulin and leptin in prostate cancer cases and controls. Eur. J. Cancer Prev.2003, 12, 309–315. Google Scholar CrossRef 675. Verheus, M.; Peeters, P.H.; Rinaldi, S.; Dossus, L.; Biessy, C.; Olsen, A.; Tjønneland, A.; Overvad, K.; Jeppesen, M.; Clavel-Chapelon, F. Serum C-peptide levels and breast cancer risk: Results from the European prospective investigation into cancer and nutrition (EPIC). Int. J. Cancer2006, 119, 659–667. Google Scholar CrossRef Green Version 676. Gunter, M.J.; Hoover, D.R.; Yu, H.; Wassertheil-Smoller, S.; Manson, J.E.; Li, J.; Harris, T.G.; Rohan, T.E.; Xue, X.; Ho, G.Y. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol. Prev. Biomark.2008, 17, 921–929. Google Scholar CrossRef Green Version 677. Kourelis, T.V.; Siegel, R.D. Metformin and cancer: New applications for an old drug. Med. Oncol.2012, 29, 1314–1327. Google Scholar CrossRef 678. Uzunlulu, M.; Caklili, O.T.; Oguz, A. Association between metabolic syndrome and cancer. Ann. Nutr. Metab.2016, 68, 173–179. Google Scholar CrossRef 679. Belfiore, A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr. Pharm. Des.2007, 13, 671–686. Google Scholar CrossRef PubMed 680. Kiselyov, V.V.; Versteyhe, S.; Gauguin, L.; De Meyts, P. Harmonic oscillator model of the insulin and IGF1 receptors’ allosteric binding and activation. Mol. Syst. Biol.2009, 5, 243. Google Scholar CrossRef PubMed 681. Scapin, G.; Dandey, V.P.; Zhang, Z.; Prosise, W.; Hruza, A.; Kelly, T.; Mayhood, T.; Strickland, C.; Potter, C.S.; Carragher, B. Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis. Nature2018, 556, 122–125. Google Scholar CrossRef PubMed 682. Cui, Y.; Andersen, D.K. Diabetes and pancreatic cancer. Endocr. Relat. Cancer2012, 19, F9–F26. Google Scholar CrossRef PubMed 683. Del Barco, S.; Vazquez-Martin, A.; Cufí, S.; Oliveras-Ferraros, C.; Bosch-Barrera, J.; Joven, J.; Martin-Castillo, B.; Menendez, J.A. Metformin: Multi-faceted protection against cancer. Oncotarget2011, 2, 896. Google Scholar CrossRef PubMed Green Version 684. Noto, H.; Goto, A.; Tsujimoto, T.; Osame, K.; Noda, M. Latest insights into the risk of cancer in diabetes. J. Diabetes Investig.2013, 4, 225–232. Google Scholar CrossRef Green Version 685. Anisimov, V.N. Metformin for aging and cancer prevention. Aging2010, 2, 760. Google Scholar CrossRef Green Version 686. Memmott, R.M.; Dennis, P.A. LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J. Clin. Oncol.2009, 27, e226. Google Scholar CrossRef 687. Baxter, R.; Brown, A.; Turtle, J. Association between serum insulin, serum somatomedin and liver receptors for human growth hormone in streptozotocin diabetes. Horm. Metab. Res.1980, 12, 377–381. Google Scholar CrossRef 688. Gallagher, E.J.; LeRoith, D. Diabetes, cancer, and metformin: Connections of metabolism and cell proliferation. Ann. N. Y. Acad. Sci.2011, 1243, 54–68. Google Scholar CrossRef 689. Friberg, E.; Mantzoros, C.S.; Wolk, A. Diabetes and risk of endometrial cancer: A population-based prospective cohort study. Cancer Epidemiol. Prev. Biomark.2007, 16, 276–280. Google Scholar CrossRef Green Version 690. Van Kruijsdijk, R.C.; Van Der Wall, E.; Visseren, F.L. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol. Prev. Biomark.2009, 18, 2569–2578. Google Scholar CrossRef Green Version 691. Somasundar, P.; Alice, K.Y.; Vona-Davis, L.; McFadden, D.W. Differential effects of leptin on cancer in vitro. J. Surg. Res.2003, 113, 50–55. Google Scholar CrossRef 692. Adekola, K.; Rosen, S.T.; Shanmugam, M. Glucose transporters in cancer metabolism. Curr. Opin. Oncol.2012, 24, 650. Google Scholar CrossRef 693. Ryu, T.Y.; Park, J.; Scherer, P.E. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab. J.2014, 38, 330. Google Scholar CrossRef Green Version 694. Fukada, T.; Yamasaki, S.; Nishida, K.; Murakami, M.; Hirano, T. Zinc homeostasis and signaling in health and diseases. JBIC J. Biol. Inorg. Chem.2011, 16, 1123–1134. Google Scholar CrossRef PubMed Green Version 695. Siebel, A.L.; Fernandez, A.Z.; El-Osta, A. Glycemic memory associated epigenetic changes. Biochem. Pharmacol.2010, 80, 1853–1859. Google Scholar CrossRef PubMed 696. Jee, S.H.; Ohrr, H.; Sull, J.W.; Yun, J.E.; Ji, M.; Samet, J.M. Fasting serum glucose level and cancer risk in Korean men and women. JAMA2005, 293, 194–202. Google Scholar CrossRef Green Version 697. Johnson, J.; Bowker, S. Intensive Glycaemic Control and Cancer Risk in Type 2 Diabetes: A Meta-Analysis of Major Trials; Springer: Berlin/Heidelberg, Germany, 2011. Google Scholar 698. Renehan, A.G.; Zwahlen, M.; Egger, M. Adiposity and cancer risk: New mechanistic insights from epidemiology. Nat. Rev. Cancer2015, 15, 484–498. Google Scholar CrossRef PubMed 699. Shu, X.; Hildebrandt, M.; Gu, J.; Tannir, N.; Matin, S.; Karam, J.; Wood, C.; Wu, X. MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity. Br. J. Cancer2017, 116, 77–84. Google Scholar CrossRef Green Version 700. Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and Cancer: A Consensus Report. CA Cancer J. Clin.2010, 60, 207–221. Google Scholar CrossRef Green Version 701. Davila, J.; Morgan, R.; Shaib, Y.; McGlynn, K.; El-Serag, H. Diabetes increases the risk of hepatocellular carcinoma in the United States: A population based case control study. Gut2005, 54, 533–539. Google Scholar CrossRef 702. Lawson, D.; Gray, J.; McKillop, C.; Clarke, J.; Lee, F.; Patrick, R. Diabetes mellitus and primary hepatocellular carcinoma. Qjm Int. J. Med.1986, 61, 945–955. Google Scholar 703. Dyson, J.; Jaques, B.; Chattopadyhay, D.; Lochan, R.; Graham, J.; Das, D.; Aslam, T.; Patanwala, I.; Gaggar, S.; Cole, M. Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol.2014, 60, 110–117. Google Scholar CrossRef 704. Wang, C.; Wang, X.; Gong, G.; Ben, Q.; Qiu, W.; Chen, Y.; Li, G.; Wang, L. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: A systematic review and meta-analysis of cohort studies. Int. J. Cancer2012, 130, 1639–1648. Google Scholar CrossRef 705. Kampf, G. Efficacy of ethanol against viruses in hand disinfection. J. Hosp. Infect.2018, 98, 331–338. Google Scholar CrossRef 706. Noureddin, M.; Rinella, M.E. Nonalcoholic Fatty Liver Disease, Diabetes, Obesity, and Hepatocellular Carcinoma. Clin. Liver Dis.2015, 19, 361–379. Google Scholar CrossRef 707. Wiencke, J.K. Impact of race/ethnicity on molecular pathways in human cancer. Nat. Rev. Cancer2004, 4, 79–84. Google Scholar CrossRef 708. Wang, P.; Kang, D.; Cao, W.; Wang, Y.; Liu, Z. Diabetes mellitus and risk of hepatocellular carcinoma: A systematic review and meta-analysis. Diabetes/Metab. Res. Rev.2012, 28, 109–122. Google Scholar CrossRef 709. Qiao, G.; Le, Y.; Li, J.; Wang, L.; Shen, F. Glycogen Synthase Kinase-3β Is Associated with the Prognosis of Hepatocellular Carcinoma and May Mediate the Influence of Type 2 Diabetes Mellitus on Hepatocellular Carcinoma. PLoS ONE2014, 9, e105624. Google Scholar CrossRef 710. Tan, Y.; Wei, S.; Zhang, W.; Yang, J.; Yang, J.; Yan, L. Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: A meta-analysis and systematic review. Cancer Manag. Res.2019, 11, 705–713. Google Scholar CrossRef Green Version 711. Kasper, J.S.; Giovannucci, E. A Meta-analysis of Diabetes Mellitus and the Risk of Prostate Cancer. Cancer Epidemiol. Biomark. Prev.2006, 15, 2056. Google Scholar CrossRef PubMed Green Version 712. Bansal, D.; Bhansali, A.; Kapil, G.; Undela, K.; Tiwari, P. Type 2 diabetes and risk of prostate cancer: A meta-analysis of observational studies. Prostate Cancer Prostatic Dis.2013, 16, 151–158. Google Scholar CrossRef PubMed 713. Waters, K.M.; Henderson, B.E.; Stram, D.O.; Wan, P.; Kolonel, L.N.; Haiman, C.A. Association of Diabetes With Prostate Cancer Risk in the Multiethnic Cohort. Am. J. Epidemiol.2009, 169, 937–945. Google Scholar CrossRef PubMed Green Version 714. Li, Q.; Kuriyama, S.; Kakizaki, M.; Yan, H.; Sone, T.; Nagai, M.; Sugawara, Y.; Ohmori-Matsuda, K.; Hozawa, A.; Nishino, Y.; et al. History of diabetes mellitus and the risk of prostate cancer: The Ohsaki Cohort Study. Cancer Causes Control2010, 21, 1025–1032. Google Scholar CrossRef PubMed 715. Ataey, A.; Jafarvand, E.; Adham, D.; Moradi-Asl, E. The relationship between obesity, overweight, and the human development index in world health organization eastern mediterranean region countries. J. Prev. Med. Public Health2020, 53, 98. Google Scholar CrossRef PubMed 716. Cohen, D.H.; LeRoith, D. Obesity, type 2 diabetes, and cancer: The insulin and IGF connection. Endocr. Relat. Cancer2012, 19, F27–F45. Google Scholar CrossRef 717. Gallagher, E.J.; LeRoith, D. Obesity and diabetes: The increased risk of cancer and cancer-related mortality. Physiol. Rev.2015, 95, 727–748. Google Scholar CrossRef Green Version 718. Kang, C.; LeRoith, D.; Gallagher, E.J. Diabetes, obesity, and breast cancer. Endocrinology2018, 159, 3801–3812. Google Scholar CrossRef Green Version 719. Pothuraju, R.; Rachagani, S.; Junker, W.M.; Chaudhary, S.; Saraswathi, V.; Kaur, S.; Batra, S.K. Pancreatic cancer associated with obesity and diabetes: An alternative approach for its targeting. J. Exp. Clin. Cancer Res.2018, 37, 319. Google Scholar CrossRef Green Version 720. Scully, T.; Ettela, A.; Gallagher, E.J.; LeRoith, D. Obesity, Type 2 Diabetes and Cancer Risk. Front. Oncol.2020, 10, 3196. Google Scholar 721. Perry, R.J.; Shulman, G.I. Mechanistic links between obesity, insulin, and cancer. Trends Cancer2020, 6, 75–78. Google Scholar CrossRef 722. Marques, R.G.; Fontaine, M.J.; Rogers, J. C-peptide: Much more than a byproduct of insulin biosynthesis. Pancreas2004, 29, 231–238. Google Scholar CrossRef PubMed 723. Jenab, M.; Riboli, E.; Cleveland, R.J.; Norat, T.; Rinaldi, S.; Nieters, A.; Biessy, C.; Tjønneland, A.; Olsen, A.; Overvad, K. Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer2007, 121, 368–376. Google Scholar CrossRef 724. Ma, J.; Li, H.; Giovannucci, E.; Mucci, L.; Qiu, W.; Nguyen, P.L.; Gaziano, J.M.; Pollak, M.; Stampfer, M.J. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: A long-term survival analysis. Lancet Oncol.2008, 9, 1039–1047. Google Scholar CrossRef Green Version 725. Bloomgarden, Z. Diabetes and cancer. Diabetes Care2001, 24, 780–781. Google Scholar 726. Bloomgarden, Z.T. Second world congress on the insulin resistance syndrome. Diabetes Care2005, 28, 1518–1523. Google Scholar CrossRef Green Version 727. Richardson, L.C.; Pollack, L.A. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat. Clin. Pract. Oncol.2005, 2, 48–53. Google Scholar CrossRef 728. Bertoni, A.G.; Saydah, S.; Brancati, F.L. Diabetes and the risk of infection-related mortality in the US. Diabetes Care2001, 24, 1044–1049. Google Scholar CrossRef PubMed Green Version 729. Theodoulou, M.; Seidman, A.D. Seminars in Oncology. In Cardiac Effects of Adjuvant Therapy for Early Breastcancer; Elsevier: Amsterdam, The Netherlands, 2003; pp. 730–739. Google Scholar 730. Wildiers, H.; Highley, M.S.; de Bruijn, E.A.; van Oosterom, A.T. Pharmacology of anticancer drugs in the elderly population. Clin. Pharmacokinet.2003, 42, 1213–1242. Google Scholar CrossRef PubMed 731. Nichols, C.R. Testicular cancer. Curr. Probl. Cancer1998, 22, 187–274. Google Scholar CrossRef 732. Donnelly, R.; Emslie-Smith, A.M.; Gardner, I.D.; Morris, A.D. Vascular complications of diabetes. BMJ2000, 320, 1062–1066. Google Scholar CrossRef PubMed 733. Flatters, S.J.; Bennett, G.J. Ethosuximide reverses paclitaxel-and vincristine-induced painful peripheral neuropathy. Pain2004, 109, 150–161. Google Scholar CrossRef 734. Bonadonna, G.; Valagussa, P. Dose-response effect of adjuvant chemotherapy in breast cancer. N. Engl. J. Med.1981, 304, 10–15. Google Scholar CrossRef PubMed 735. DeVita, V.T.; Hubbard, S.M.; Longo, D.L. The chemotherapy of lymphomas: Looking back, moving forward—the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res.1987, 47, 5810–5824. Google Scholar 736. Childs, B.B.; Cypress, M.; Spollett, G. Complete Nurse’s Guide to Diabetes Care; American Diabetes Association: Arlington County, VI, USA, 2017. Google Scholar 737. Clement, S.; Braithwaite, S.; Magee, M.; Ahmann, A.; Smith, E.; Schafer, R.; Hirsch, I. Erratum: Management of diabetes and hyperglycemia in hospitals (Technical Review). Diabetes Care2004, 27, 553–591. Google Scholar CrossRef PubMed Green Version 738. Jiralerspong, S.; Palla, S.L.; Giordano, S.H.; Meric-Bernstam, F.; Liedtke, C.; Barnett, C.M.; Hsu, L.; Hung, M.-C.; Hortobagyi, G.N.; Gonzalez-Angulo, A.M. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol.2009, 27, 3297. Google Scholar CrossRef PubMed Green Version 739. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin.2015, 65, 5–29. Google Scholar CrossRef PubMed 740. Tan, B.X.; Yao, W.X.; Ge, J.; Peng, X.C.; Du, X.B.; Zhang, R.; Yao, B.; Xie, K.; Li, L.H.; Dong, H. Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer2011, 117, 5103–5111. Google Scholar CrossRef PubMed 741. Volgi, J.R.; Baldwin, D., Jr. Glucocorticoid therapy and diabetes management. Nurs. Clin. N. Am.2001, 36, 333–339. Google Scholar 742. Braithwaite, S.S.; Barr, W.G.; Rahman, A.; Quddusi, S. Managing diabetes during glucocorticoid therapy: How to avoid metabolic emergencies. Postgrad. Med.1998, 104, 163–176. Google Scholar CrossRef 743. Hirsch, I.; Braithwaite, S.; Verderese, C. Practical Management of Inpatient Hyperglycemia; LakevilleConn Hilliard Publishing: Lakeville, CT, USA, 2005; pp. 1–41. Google Scholar 744. Trence, D.L. Management of patients on chronic glucocorticoid therapy: An endocrine perspective. Prim. Care Clin. Off. Pract.2003, 30, 593–605. Google Scholar CrossRef 745. McCoubrie, R.; Jeffrey, D.; Paton, C.; Dawes, L. Managing diabetes mellitus in patients with advanced cancer: A case note audit and guidelines. Eur. J. Cancer Care2005, 14, 244–248. Google Scholar CrossRef 746. Medina-Bolivar, F.; Condori, J.; Rimando, A.M.; Hubstenberger, J.; Shelton, K.; O’Keefe, S.F.; Bennett, S.; Dolan, M.C. Production and secretion of resveratrol in hairy root cultures of peanut. Phytochemistry2007, 68, 1992–2003. Google Scholar CrossRef 747. Tian, B.; Liu, J. Resveratrol: A review of plant sources, synthesis, stability, modification and food application. J. Sci. Food Agric.2020, 100, 1392–1404. Google Scholar CrossRef 748. Lançon, A.; Hanet, N.; Jannin, B.; Delmas, D.; Heydel, J.-M.; Lizard, G.; Chagnon, M.-C.; Artur, Y.; Latruffe, N. Resveratrol in human hepatoma HepG2 cells: Metabolism and inducibility of detoxifying enzymes. Drug Metab. Dispos.2007, 35, 699–703. Google Scholar CrossRef PubMed Green Version 749. Jeandet, P.; Douillet-Breuil, A.-C.; Bessis, R.; Debord, S.; Sbaghi, M.; Adrian, M. Phytoalexins from the Vitaceae: Biosynthesis, phytoalexin gene expression in transgenic plants, antifungal activity, and metabolism. J. Agric. Food Chem.2002, 50, 2731–2741. Google Scholar CrossRef 750. Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A double-edged sword in health benefits. Biomedicines2018, 6, 91. Google Scholar CrossRef Green Version 751. Li, L.; Qiu, R.L.; Lin, Y.; Cai, Y.; Bian, Y.; Fan, Y.; Gao, X.J. Resveratrol suppresses human cervical carcinoma cell proliferation and elevates apoptosis via the mitochondrial and p53 signaling pathways. Oncol. Lett.2018, 15, 9845–9851. Google Scholar CrossRef Green Version 752. Li, D.; Wang, G.; Jin, G.; Yao, K.; Zhao, Z.; Bie, L.; Guo, Y.; Li, N.; Deng, W.; Chen, X. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int. J. Mol. Med.2019, 43, 630–640. Google Scholar CrossRef Green Version 753. Öztürk, Y.; Günaydın, C.; Yalçın, F.; Nazıroğlu, M.; Braidy, N. Resveratrol enhances apoptotic and oxidant effects of paclitaxel through TRPM2 channel activation in DBTRG glioblastoma cells. Oxid. Med. Cell. Longev.2019, 2019, 4619865. Google Scholar CrossRef 754. Hoca, M.; Becer, E.; Kabadayı, H.; Yücecan, S.; Vatansever, H.S. The effect of resveratrol and quercetin on epithelial-mesenchymal transition in pancreatic cancer stem cell. Nutr. Cancer2020, 72, 1231–1242. Google Scholar CrossRef 755. Zhao, Y.; Cao, Y.; Sun, J.; Liang, Z.; Wu, Q.; Cui, S.; Zhi, D.; Guo, S.; Zhen, Y.; Zhang, S. Anti-breast cancer activity of resveratrol encapsulated in liposomes. J. Mater. Chem. B2020, 8, 27–37. Google Scholar CrossRef 756. Alobaedi, O.H.; Talib, W.H.; Basheti, I.A. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pac. J. Trop. Med.2017, 10, 400–408. Google Scholar CrossRef PubMed 757. Ismail, N.; Abdel–Mottaleb, Y.; Ahmed, A.A.E.; El-Maraghy, N.N. Novel combination of thymoquinone and resveratrol enhances anticancer effect on hepatocellular carcinoma cell line. Future J. Pharm. Sci.2018, 4, 41–46. Google Scholar CrossRef 758. Rai, G.; Mishra, S.; Suman, S.; Shukla, Y. Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight. Phytomedicine2016, 23, 233–242. Google Scholar CrossRef 759. Zhang, A.J.; Rimando, A.M.; Mizuno, C.S.; Mathews, S.T. α-Glucosidase inhibitory effect of resveratrol and piceatannol. J. Nutr. Biochem.2017, 47, 86–93. Google Scholar CrossRef 760. Rimando, A.M.; Nagmani, R.; Feller, D.R.; Yokoyama, W. Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor α-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J. Agric. Food Chem.2005, 53, 3403–3407. Google Scholar CrossRef 761. Yang, D.K.; Kang, H.-S. Anti-diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats. Biomol. Ther.2018, 26, 130. Google Scholar CrossRef Green Version 762. Agarwal, A.; Kasinathan, A.; Ganesan, R.; Balasubramanian, A.; Bhaskaran, J.; Suresh, S.; Srinivasan, R.; Aravind, K.; Sivalingam, N. Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species–independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells. Nutr. Res.2018, 51, 67–81. Google Scholar CrossRef PubMed 763. Muangnoi, C.; Jithavech, P.; Ratnatilaka Na Bhuket, P.; Supasena, W.; Wichitnithad, W.; Towiwat, P.; Niwattisaiwong, N.; Haworth, I.S.; Rojsitthisak, P. A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin. Biosci. Biotechnol. Biochem.2018, 82, 1301–1308. Google Scholar CrossRef PubMed Green Version 764. Talib, W.H.; Al-Hadid, S.A.; Ali, M.B.W.; Al-Yasari, I.H.; Abd Ali, M.R. Role of curcumin in regulating p53 in breast cancer: An overview of the mechanism of action. Breast Cancer Targets Ther.2018, 10, 207. Google Scholar CrossRef Green Version 765. Ismail, N.I.; Othman, I.; Abas, F.; H Lajis, N.; Naidu, R. Mechanism of apoptosis induced by curcumin in colorectal cancer. Int. J. Mol. Sci.2019, 20, 2454. Google Scholar CrossRef Green Version 766. Kunnumakkara, A.B.; Bordoloi, D.; Padmavathi, G.; Monisha, J.; Roy, N.K.; Prasad, S.; Aggarwal, B.B. Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases. Br. J. Pharmacol.2017, 174, 1325–1348. Google Scholar CrossRef Green Version 767. Xu, X.-Y.; Meng, X.; Li, S.; Gan, R.-Y.; Li, Y.; Li, H.-B. Bioactivity, health benefits, and related molecular mechanisms of curcumin: Current progress, challenges, and perspectives. Nutrients2018, 10, 1553. Google Scholar CrossRef PubMed Green Version 768. Ahmed, K.; Zaidi, S.F.; Cui, Z.G.; Zhou, D.; Saeed, S.A.; Inadera, H. Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer. Oncol. Lett.2019, 18, 487–498. Google Scholar CrossRef Green Version 769. Su, P.; Yang, Y.; Wang, G.; Chen, X.; Ju, Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int. J. Oncol.2018, 53, 1343–1353. Google Scholar CrossRef PubMed 770. Villegas, I.; Sánchez-Fidalgo, S.; de la Lastra, C.A. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol. Nutr. Food Res.2011, 55, 259–267. Google Scholar CrossRef PubMed 771. Jung, E.M.; Lim, J.H.; Lee, T.J.; Park, J.-W.; Choi, K.S.; Kwon, T.K. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis2005, 26, 1905–1913. Google Scholar CrossRef PubMed Green Version 772. Babushkina, E.A.; Belokopytova, L.V.; Grachev, A.M.; Meko, D.M.; Vaganov, E.A. Variation of the hydrological regime of Bele-Shira closed basin in Southern Siberia and its reflection in the radial growth of Larix sibirica. Reg. Environ. Chang.2017, 17, 1725–1737. Google Scholar CrossRef Green Version 773. Song, G.; Mao, Y.; Cai, Q.; Yao, L.; Ouyang, G.; Bao, S. Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression. Braz. J. Med. Biol. Res.2005, 38, 1791–1798. Google Scholar CrossRef Green Version 774. Sun, Y.; Liu, L.; Wang, Y.; He, A.; Hu, H.; Zhang, J.; Han, M.; Huang, Y. Curcumin inhibits the proliferation and invasion of MG-63 cells through inactivation of the p-JAK2/p-STAT3 pathway. Oncotargets Ther.2019, 12, 2011. Google Scholar CrossRef Green Version 775. Tomeh, M.A.; Hadianamrei, R.; Zhao, X. A review of curcumin and its derivatives as anticancer agents. Int. J. Mol. Sci.2019, 20, 1033. Google Scholar CrossRef PubMed Green Version 776. Den Hartogh, D.J.; Gabriel, A.; Tsiani, E. Antidiabetic properties of curcumin I: Evidence from in vitro studies. Nutrients2020, 12, 118. Google Scholar CrossRef Green Version 777. Den Hartogh, D.J.; Gabriel, A.; Tsiani, E. Antidiabetic properties of curcumin II: Evidence from in vivo studies. Nutrients2020, 12, 58. Google Scholar CrossRef Green Version 778. Abdelsamia, E.M.; Khaleel, S.A.; Balah, A.; Baky, N.A.A. Curcumin augments the cardioprotective effect of metformin in an experimental model of type I diabetes mellitus; Impact of Nrf2/HO-1 and JAK/STAT pathways. Biomed. Pharmacother.2019, 109, 2136–2144. Google Scholar CrossRef 779. Dajani, E.; Shahwan, T.; Dajani, N. Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): A complementary drug with historical and clinical significance. J. Physiol. Pharm.2016, 67, 801–817. Google Scholar 780. Younus, H. Molecular and Therapeutic: Actions of Thymoquinone; Springer: Berlin/Heidelberg, Germany, 2018. Google Scholar 781. Ahmad, A.; Husain, A.; Mujeeb, M.; Khan, S.A.; Najmi, A.K.; Siddique, N.A.; Damanhouri, Z.A.; Anwar, F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac. J. Trop. Biomed.2013, 3, 337–352. Google Scholar CrossRef Green Version 782. Aslan, M.; Afşar, E.; Kırımlıoglu, E.; Çeker, T.; Yılmaz, Ç. Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress. Nutr. Cancer2020, 73, 460–472. Google Scholar CrossRef PubMed 783. Darakhshan, S.; Pour, A.B.; Colagar, A.H.; Sisakhtnezhad, S. Thymoquinone and its therapeutic potentials. Pharmacol. Res.2015, 95, 138–158. Google Scholar CrossRef PubMed 784. Laskar, A.A.; Khan, M.A.; Askari, F.; Younus, H. Thymoquinone binds and activates human salivary aldehyde dehydrogenase: Potential therapy for the mitigation of aldehyde toxicity and maintenance of oral health. Int. J. Biol. Macromol.2017, 103, 99–110. Google Scholar CrossRef 785. Motaghed, M.; Al-Hassan, F.M.; Hamid, S.S. Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7. Pharmacogn. Res.2013, 5, 200. Google Scholar 786. El-Sheikh, A.A.; Morsy, M.A.; Abdalla, A.M.; Hamouda, A.H.; Alhaider, I.A. Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats. Mediat. Inflamm.2015, 2015, 859383. Google Scholar CrossRef Green Version 787. Kundu, J.; Choi, B.Y.; Jeong, C.-H.; Kundu, J.K.; Chun, K.-S. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2-and Src-mediated phosphorylation of EGF receptor tyrosine kinase. Oncol. Rep.2014, 32, 821–828. Google Scholar CrossRef PubMed Green Version 788. Woo, C.C.; Loo, S.Y.; Gee, V.; Yap, C.W.; Sethi, G.; Kumar, A.P.; Tan, K.H.B. Anticancer activity of thymoquinone in breast cancer cells: Possible involvement of PPAR-γ pathway. Biochem. Pharmacol.2011, 82, 464–475. Google Scholar CrossRef PubMed 789. Talib, W.H. Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci. Pharm.2017, 85, 27. Google Scholar CrossRef Green Version 790. Pelegrin, S.; Galtier, F.; Chalançon, A.; Gagnol, J.P.; Barbanel, A.M.; Pélissier, Y.; Larroque, M.; Lepape, S.; Faucanié, M.; Gabillaud, I. Effects of Nigella sativa seeds (black cumin) on insulin secretion and lipid profile: A pilot study in healthy volunteers. Br. J. Clin. Pharmacol.2019, 85, 1607–1611. Google Scholar CrossRef 791. Khalil, P.; Masood, S.; Rehman, A.U.; Khalil, F.; Nawaf, J. Preventive Role of Thymoquinone against Certain Chronic Health Issues: A Review. Int. J. Nutr. Sci.2020. Google Scholar CrossRef 792. Durvasula, R.V.; Petermann, A.T.; Hiromura, K.; Blonski, M.; Pippin, J.; Mundel, P.; Pichler, R.; Griffin, S.; Couser, W.G.; Shankland, S.J. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int.2004, 65, 30–39. Google Scholar CrossRef Green Version 793. Montazeri, R.S.; Fatahi, S.; Sohouli, M.H.; Abu-Zaid, A.; Santos, H.O.; Găman, M.A.; Shidfar, F. The effect of nigella sativa on biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials. J. Food Biochem.2021, e13625. Google Scholar CrossRef 794. Lambert, J.D.; Lee, M.J.; Lu, H.; Meng, X.; Hong, J.J.; Seril, D.N.; Sturgill, M.G.; Yang, C.S. Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice. J. Nutr.2003, 133, 4172–4177. Google Scholar CrossRef 795. Nagle, D.G.; Ferreira, D.; Zhou, Y.-D. Epigallocatechin-3-gallate (EGCG): Chemical and biomedical perspectives. Phytochemistry2006, 67, 1849–1855. Google Scholar CrossRef Green Version 796. Rodríguez-Carrasco, Y.; Gaspari, A.; Graziani, G.; Santini, A.; Ritieni, A. Fast analysis of polyphenols and alkaloids in cocoa-based products by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS). Food Res. Int.2018, 111, 229–236. Google Scholar CrossRef 797. Chopade, V.; Phatak, A.; Upaganlawar, A.; Tankar, A. Green tea (Camellia sinensis): Chemistry, traditional, medicinal uses and its pharmacological activities-a review. Pharmacogn. Rev.2008, 2, 157. Google Scholar 798. Katiyar, S.K.; Elmets, C.A. Green tea polyphenolic antioxidants and skin photoprotection. Int. J. Oncol.2001, 18, 1307–1313. Google Scholar CrossRef 799. Musial, C.; Kuban-Jankowska, A.; Gorska-Ponikowska, M. Beneficial Properties of Green Tea Catechins. Int. J. Mol. Sci.2020, 21, 1744. Google Scholar CrossRef PubMed Green Version 800. Wang, Y.-Q.; Lu, J.-L.; Liang, Y.-R.; Li, Q.-S. Suppressive effects of EGCG on cervical cancer. Molecules2018, 23, 2334. Google Scholar CrossRef Green Version 801. Ho, H.C.; Huang, C.C.; Lu, Y.T.; Yeh, C.M.; Ho, Y.T.; Yang, S.F.; Hsin, C.H.; Lin, C.W. Epigallocatechin-3-gallate inhibits migration of human nasopharyngeal carcinoma cells by repressing MMP-2 expression. J. Cell. Physiol.2019, 234, 20915–20924. Google Scholar CrossRef PubMed 802. Pal, D.; Sur, S.; Roy, R.; Mandal, S.; Kumar Panda, C. Epigallocatechin gallate in combination with eugenol or amarogentin shows synergistic chemotherapeutic potential in cervical cancer cell line. J. Cell. Physiol.2019, 234, 825–836. Google Scholar CrossRef PubMed Green Version 803. Yuan, C.H.; Horng, C.T.; Lee, C.F.; Chiang, N.N.; Tsai, F.J.; Lu, C.C.; Chiang, J.H.; Hsu, Y.M.; Yang, J.S.; Chen, F.A. Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling. Environ. Toxicol.2017, 32, 845–855. Google Scholar CrossRef PubMed 804. Chuu, C.-P.; Chen, R.-Y.; Kokontis, J.M.; Hiipakka, R.A.; Liao, S. Suppression of androgen receptor signaling and prostate specific antigen expression by (−)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett.2009, 275, 86–92. Google Scholar CrossRef PubMed Green Version 805. Xu, L.; Li, W.; Chen, Z.; Guo, Q.; Wang, C.; Santhanam, R.K.; Chen, H. Inhibitory effect of epigallocatechin-3-O-gallate on α-glucosidase and its hypoglycemic effect via targeting PI3K/AKT signaling pathway in L6 skeletal muscle cells. Int. J. Biol. Macromol.2019, 125, 605–611. Google Scholar CrossRef 806. Lin, Y.; Shi, D.; Su, B.; Wei, J.; Găman, M.A.; Sedanur Macit, M.; Borges do Nascimento, I.J.; Guimaraes, N.S. The effect of green tea supplementation on obesity: A systematic review and dose–response meta-analysis of randomized controlled trials. Phytother. Res.2020, 34, 2459–2470. Google Scholar CrossRef 807. Lanzotti, V. The analysis of onion and garlic. J. Chromatogr. A2006, 1112, 3–22. Google Scholar CrossRef Green Version 808. Chen, H.; Zhu, B.; Zhao, L.; Liu, Y.; Zhao, F.; Feng, J.; Jin, Y.; Sun, J.; Geng, R.; Wei, Y. Allicin inhibits proliferation and invasion in vitro and in vivo via SHP-1-mediated STAT3 signaling in cholangiocarcinoma. Cell. Physiol. Biochem.2018, 47, 641–653. Google Scholar CrossRef 809. Huang, W.L.; Wu, S.F.; Xu, S.T.; Ma, Y.C.; Wang, R.; Jin, S.; Zhou, S. Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF-κB signaling pathway. J. Food Sci.2020, 85, 1924–1931. Google Scholar CrossRef 810. Yang, Z.; Du, J.; Zhu, J.; Rong, Y.; Chen, S.; Yu, L.; Deng, X.; Zhang, X.; Sheng, H.; Yang, L. Allicin Inhibits Proliferation by Decreasing IL-6 and IFN-β in HCMV-Infected Glioma Cells. Cancer Manag. Res.2020, 12, 7305. Google Scholar CrossRef 811. Schultz, C.R.; Gruhlke, M.C.; Slusarenko, A.J.; Bachmann, A.S. Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells. J. Nat. Prod.2020, 83, 2518–2527. Google Scholar CrossRef PubMed 812. Jobani, B.M.; Najafzadeh, N.; Mazani, M.; Arzanlou, M.; Vardin, M.M. Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+ versus CD117+ melanoma cells. Phytomedicine2018, 48, 161–169. Google Scholar CrossRef PubMed 813. Țigu, A.B.; Toma, V.-A.; Moț, A.C.; Jurj, A.; Moldovan, C.S.; Fischer-Fodor, E.; Berindan-Neagoe, I.; Pârvu, M. The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells. Molecules2020, 25, 1947. Google Scholar CrossRef PubMed 814. Arellano-Buendía, A.S.; Castañeda-Lara, L.G.; Loredo-Mendoza, M.L.; García-Arroyo, F.E.; Rojas-Morales, P.; Argüello-García, R.; Juárez-Rojas, J.G.; Tapia, E.; Pedraza-Chaverri, J.; Sánchez-Lozada, L.G. Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes. Antioxidants2020, 9, 1134. Google Scholar CrossRef 815. Mandal, S.K.; Das, A.; Dey, S.; Sahoo, U.; Bose, S.; Bose, A.; Dhiman, N.; Madan, S.; Ramadan, M.A. Bioactivities of Allicin and related organosulfur compounds from garlic: Overview of the literature since 2010. Egypt. J. Chem.2019, 62, 1–11. Google Scholar CrossRef 816. Li, L.; Sheng, X.; Zhao, S.; Zou, L.; Han, X.; Gong, Y.; Yuan, H.; Shi, L.; Guo, L.; Jia, T. Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia. Purinergic Signal.2017, 13, 559–568. Google Scholar CrossRef PubMed Green Version 817. Lu, P.; Zhao, X.; Cui, T. Full Length Research Paper Production of emodin from Aspergillus ochraceus at preparative scale. Afr. J. Biotechnol.2010, 9. Available online: https://www.ajol.info/index.php/ajb/article/view/77969 (accessed on 9 April 2021). 818. Shun-Hua, L.; Lin, L.; Ru-Nan, Y.; Liang, S.-D. Compounds of traditional Chinese medicine and neuropathic pain. Chin. J. Nat. Med.2020, 18, 28–35. Google Scholar 819. Talib, W.H.; Alsalahat, I.; Daoud, S.; Abutayeh, R.F.; Mahmod, A.I. Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation. Molecules2020, 25, 5319. Google Scholar CrossRef PubMed 820. Tang, T.; Yin, L.; Yang, J.; Shan, G. Emodin, an anthraquinone derivative from Rheum officinale Baill, enhances cutaneous wound healing in rats. Eur. J. Pharmacol.2007, 567, 177–185. Google Scholar CrossRef PubMed 821. Huang, H.-C.; Chang, J.-H.; Tung, S.-F.; Wu, R.-T.; Foegh, M.L.; Chu, S.-H. Immunosuppressive effect of emodin, a free radical generator. Eur. J. Pharmacol.1992, 211, 359–364. Google Scholar CrossRef 822. Huei-Chen, H.; Shu-Hsun, C.; Chao, P.-D.L. Vasorelaxants from Chinese herbs, emodin and scoparone, possess immunosuppressive properties. Eur. J. Pharmacol.1991, 198, 211–213. Google Scholar CrossRef 823. Kaneshiro, T.; Morioka, T.; Inamine, M.; Kinjo, T.; Arakaki, J.; Chiba, I.; Sunagawa, N.; Suzui, M.; Yoshimi, N. Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation. Eur. J. Pharmacol.2006, 553, 46–53. Google Scholar CrossRef 824. Zhu, S.; Wang, Y.; Wang, X.; Li, J.; Hu, F. Emodin inhibits ATP-induced IL-1β secretion, ROS production and phagocytosis attenuation in rat peritoneal macrophages via antagonizing P2X7 receptor. Pharm. Biol.2014, 52, 51–57. Google Scholar CrossRef PubMed 825. Hsu, S.-C.; Chung, J.-G. Anticancer potential of emodin. BioMedicine2012, 2, 108–116. Google Scholar CrossRef PubMed 826. Dong, X.; Fu, J.; Yin, X.; Cao, S.; Li, X.; Lin, L.; Huyiligeqi; Ni, J. Emodin: A review of its pharmacology, toxicity and pharmacokinetics. Phytother. Res.2016, 30, 1207–1218. Google Scholar CrossRef 827. Mukund, V.; Mukund, D.; Sharma, V.; Mannarapu, M.; Alam, A. Genistein: Its role in metabolic diseases and cancer. Crit. Rev. Oncol. Hematol.2017, 119, 13–22. Google Scholar CrossRef 828. Spagnuolo, C.; Russo, G.L.; Orhan, I.E.; Habtemariam, S.; Daglia, M.; Sureda, A.; Nabavi, S.F.; Devi, K.P.; Loizzo, M.R.; Tundis, R. Genistein and cancer: Current status, challenges, and future directions. Adv. Nutr.2015, 6, 408–419. Google Scholar CrossRef PubMed Green Version 829. Chodon, D.; Banu, S.M.; Padmavathi, R.; Sakthisekaran, D. Inhibition of cell proliferation and induction of apoptosis by genistein in experimental hepatocellular carcinoma. Mol. Cell. Biochem.2007, 297, 73. Google Scholar CrossRef PubMed 830. Tatsuta, M.; Iishi, H.; Baba, M.; Yano, H.; Uehara, H.; Nakaizumi, A. Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine in Wistar rats. Int. J. Cancer1999, 80, 396–399. Google Scholar CrossRef 831. Estrela, J.M.; Mena, S.; Obrador, E.; Benlloch, M.; Castellano, G.; Salvador, R.; Dellinger, R.W. Polyphenolic phytochemicals in cancer prevention and therapy: Bioavailability versus bioefficacy. J. Med. Chem.2017, 60, 9413–9436. Google Scholar CrossRef 832. Yousefi, H.; Alihemmati, A.; Karimi, P.; Alipour, M.R.; Habibi, P.; Ahmadiasl, N. Effect of genistein on expression of pancreatic SIRT1, inflammatory cytokines and histological changes in ovariectomized diabetic rat. Iran. J. Basic Med. Sci.2017, 20, 423. Google Scholar 833. Luo, J.; Wang, A.; Zhen, W.; Wang, Y.; Si, H.; Jia, Z.; Alkhalidy, H.; Cheng, Z.; Gilbert, E.; Xu, B. Phytonutrient genistein is a survival factor for pancreatic β-cells via GPR30-mediated mechanism. J. Nutr. Biochem.2018, 58, 59–70. Google Scholar CrossRef 834. Talib, W.H.; Al Kury, L.T. Parthenolide inhibits tumor-promoting effects of nicotine in lung cancer by inducing P53-dependent apoptosis and inhibiting VEGF expression. Biomed. Pharmacother.2018, 107, 1488–1495. Google Scholar CrossRef 835. Williams, B.; Lees, F.; Tsangari, H.; Hutchinson, M.; Perilli, E.; Crotti, T. Assessing the Effects of Parthenolide on Inflammation, Bone Loss, and Glial Cells within a Collagen Antibody-Induced Arthritis Mouse Model. Mediat. Inflamm.2020, 2020, 6245798. Google Scholar CrossRef PubMed 836. Aljancic, I.; Vajs, V.; Bulatovic, V.; Menkovic, N.; Milosavljevic, S. Parthenolide from the aerial parts of Tanacetum larvatum. Biochem. Syst. Ecol.2001, 29, 655–658. Google Scholar CrossRef 837. Che, S.-T.; Bie, L.; Li, X.; Qi, H.; Yu, P.; Zuo, L. Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells. Int. J. Ophthalmol.2019, 12, 1531. Google Scholar CrossRef PubMed 838. Tadić, V.; Živković, J.; Bigović, D.; Žugić, A. Variation of parthenolide and phenolic compounds content in different parts of Tanacetum parthenium (L.) Schulz Bip. Asteraceae during 18 months storage. Lek. Sirovine2019, 35–39. Google Scholar CrossRef Green Version 839. Pajak, B.; Gajkowska, B.; Orzechowski, A. Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells. Folia Histochem. Cytobiol.2008, 46, 129–135. Google Scholar CrossRef PubMed Green Version 840. Kim, J.-H.; Liu, L.; Lee, S.-O.; Kim, Y.-T.; You, K.-R.; Kim, D.-G. Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res.2005, 65, 6312–6320. Google Scholar CrossRef PubMed Green Version 841. Carlisi, D.; Buttitta, G.; Di Fiore, R.; Scerri, C.; Drago-Ferrante, R.; Vento, R.; Tesoriere, G. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis. Cell Death Dis.2016, 7, e2194. Google Scholar CrossRef PubMed Green Version 842. Nakabayashi, H.; Shimizu, K. Involvement of Akt/NF-κB pathway in antitumor effects of parthenolide on glioblastoma cells in vitro and in vivo. BMC Cancer2012, 12, 1–11. Google Scholar CrossRef Green Version 843. Yip-Schneider, M.T.; Wu, H.; Stantz, K.; Agaram, N.; Crooks, P.A.; Schmidt, C.M. Dimethylaminoparthenolide and gemcitabine: A survival study using a genetically engineered mouse model of pancreatic cancer. BMC Cancer2013, 13, 194. Google Scholar CrossRef Green Version 844. Hao, Q.; Wang, B.; Zhang, W.; Qiu, W.; Liu, Q.; Li, X. NF-κB inhibitor parthenolide promotes renal tubules albumin uptake in type 2 diabetic nephropathy. Chin. Med. Sci. J.2020, 35, 31–42. Google Scholar 845. Kim, C.Y.; Kang, B.; Hong, J.; Choi, H.-S. Parthenolide inhibits lipid accumulation via activation of Nrf2/Keap1 signaling during adipocyte differentiation. Food Sci. Biotechnol.2020, 29, 431–440. Google Scholar CrossRef 846. Imran, M.; Rauf, A.; Abu-Izneid, T.; Nadeem, M.; Shariati, M.A.; Khan, I.A.; Imran, A.; Orhan, I.E.; Rizwan, M.; Atif, M. Luteolin, a flavonoid, as an anticancer agent: A review. Biomed. Pharmacother.2019, 112, 108612. Google Scholar CrossRef 847. Lim, S.H.; Jung, S.K.; Byun, S.; Lee, E.J.; Hwang, J.A.; Seo, S.G.; Kim, Y.A.; Yu, J.G.; Lee, K.W.; Lee, H.J. Luteolin suppresses UVB-induced photoageing by targeting JNK1 and p90RSK2. J. Cell. Mol. Med.2013, 17, 672–680. Google Scholar CrossRef 848. Wang, H.; Yang, L.; Zu, Y.; Zhao, X. Microwave-assisted simultaneous extraction of luteolin and apigenin from tree peony pod and evaluation of its antioxidant activity. Sci. World J.2014, 2014, 506971. Google Scholar CrossRef PubMed Green Version 849. Lin, D.; Kuang, G.; Wan, J.; Zhang, X.; Li, H.; Gong, X.; Li, H. Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncol. Rep.2017, 37, 895–902. Google Scholar CrossRef PubMed Green Version 850. Jiang, Z.-Q.; Li, M.-H.; Qin, Y.-M.; Jiang, H.-Y.; Zhang, X.; Wu, M.-H. Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of MicroRNA-34a-5p. Int. J. Mol. Sci.2018, 19, 447. Google Scholar CrossRef PubMed Green Version 851. Lee, Y.J.; Lim, T.; Han, M.S.; Lee, S.-H.; Baek, S.H.; Nan, H.-Y.; Lee, C. Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells. Oncol. Rep.2017, 37, 1219–1226. Google Scholar CrossRef Green Version 852. Yu, Q.; Zhang, M.; Ying, Q.; Xie, X.; Yue, S.; Tong, B.; Wei, Q.; Bai, Z.; Ma, L. Decrease of AIM2 mediated by luteolin contributes to non-small cell lung cancer treatment. Cell Death Dis.2019, 10, 1–14. Google Scholar CrossRef PubMed 853. Lin, Y.; Shi, R.; Wang, X.; Shen, H.-M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets2008, 8, 634–646. Google Scholar CrossRef 854. Horinaka, M.; Yoshida, T.; Shiraishi, T.; Nakata, S.; Wakada, M.; Nakanishi, R.; Nishino, H.; Matsui, H.; Sakai, T. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene2005, 24, 7180–7189. Google Scholar CrossRef Green Version 855. Cai, X.; Ye, T.; Liu, C.; Lu, W.; Lu, M.; Zhang, J.; Wang, M.; Cao, P. Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol. Vitr.2011, 25, 1385–1391. Google Scholar CrossRef 856. Ambasta, R.K.; Jha, S.K.; Kumar, D.; Sharma, R.; Jha, N.K.; Kumar, P. Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules. J. Transl. Med.2015, 13, 307. Google Scholar CrossRef 857. Ambasta, R.K.; Gupta, R.; Kumar, D.; Bhattacharya, S.; Sarkar, A.; Kumar, P. Can luteolin be a therapeutic molecule for both colon cancer and diabetes? Brief. Funct. Genom.2019, 18, 230–239. Google Scholar CrossRef 858. Rauf, A.; Imran, M.; Khan, I.A.; ur-Rehman, M.; Gilani, S.A.; Mehmood, Z.; Mubarak, M.S. Anticancer potential of quercetin: A comprehensive review. Phytother. Res.2018, 32, 2109–2130. Google Scholar CrossRef PubMed 859. Grande, F.; Parisi, O.I.; Mordocco, R.A.; Rocca, C.; Puoci, F.; Scrivano, L.; Quintieri, A.M.; Cantafio, P.; Ferla, S.; Brancale, A. Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization. Eur. J. Pharm. Sci.2016, 82, 161–170. Google Scholar CrossRef PubMed 860. Iacopetta, D.; Grande, F.; Caruso, A.; Mordocco, R.A.; Plutino, M.R.; Scrivano, L.; Ceramella, J.; Muià, N.; Saturnino, C.; Puoci, F. New insights for the use of quercetin analogs in cancer treatment. Future Med. Chem.2017, 9, 2011–2028. Google Scholar CrossRef PubMed 861. Kim, W.K.; Bang, M.H.; Kim, E.S.; Kang, N.E.; Jung, K.C.; Cho, H.J.; Park, J.H. Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J. Nutr. Biochem.2005, 16, 155–162. Google Scholar CrossRef 862. Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr.2006, 136, 2715–2721. Google Scholar CrossRef Green Version 863. Liao, H.; Bao, X.; Zhu, J.; Qu, J.; Sun, Y.; Ma, X.; Wang, E.; Guo, X.; Kang, Q.; Zhen, Y. O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway. Chem. Biol. Interact.2015, 242, 91–98. Google Scholar CrossRef 864. Ranganathan, S.; Halagowder, D.; Sivasithambaram, N.D. Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS ONE2015, 10, e0141370. Google Scholar CrossRef Green Version 865. Minaei, A.; Sabzichi, M.; Ramezani, F.; Hamishehkar, H.; Samadi, N. Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. Mol. Biol. Rep.2016, 43, 99–105. Google Scholar CrossRef 866. Chang, J.-H.; Lai, S.-L.; Chen, W.-S.; Hung, W.-Y.; Chow, J.-M.; Hsiao, M.; Lee, W.-J.; Chien, M.-H. Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways. Biochim. Biophys. Acta (BBA) Mol. Cell Res.2017, 1864, 1746–1758. Google Scholar CrossRef 867. Ali, H.; Dixit, S. Quercetin attenuates the development of 7, 12-dimethyl benz (a) anthracene (DMBA) and croton oil-induced skin cancer in mice. J. Biomed. Res.2015, 29, 139. Google Scholar 868. Bule, M.; Abdurahman, A.; Nikfar, S.; Abdollahi, M.; Amini, M. Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies. Food Chem. Toxicol.2019, 125, 494–502. Google Scholar CrossRef PubMed 869. Srinivasan, P.; Vijayakumar, S.; Kothandaraman, S.; Palani, M. Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J. Pharm. Anal.2018, 8, 109–118. Google Scholar CrossRef 870. An, Y.-W.; Jin, H.-T.; Yuan, B.; Wang, J.-C.; Wang, C.; Liu, H.-Q. Research progress of berberine mediated photodynamic therapy. Oncol. Lett.2021, 21, 1–10. Google Scholar CrossRef 871. Yun, D.; Yoon, S.Y.; Park, S.J.; Park, Y.J. The Anticancer Effect of Natural Plant Alkaloid Isoquinolines. Int. J. Mol. Sci.2021, 22, 1653. Google Scholar CrossRef 872. Xiong, P.; Niu, L.; Talaei, S.; Kord-Varkaneh, H.; Clark, C.C.; Găman, M.-A.; Rahmani, J.; Dorosti, M.; Mousavi, S.M.; Zarezadeh, M. The effect of berberine supplementation on obesity indices: A dose–response meta-analysis and systematic review of randomized controlled trials. Complement. Ther. Clin. Pract.2020, 39, 101113. Google Scholar CrossRef 873. Costea, T.; Hudiță, A.; Ciolac, O.-A.; Gălățeanu, B.; Ginghină, O.; Costache, M.; Ganea, C.; Mocanu, M.-M. Chemoprevention of colorectal cancer by dietary compounds. Int. J. Mol. Sci.2018, 19, 3787. Google Scholar CrossRef PubMed Green Version 874. Ramprasath, V.R.; Awad, A.B. Role of phytosterols in cancer prevention and treatment. J. Aoac Int.2015, 98, 735–738. Google Scholar CrossRef 875. Xiong, M.; Huang, Y.; Liu, Y.; Huang, M.; Song, G.; Ming, Q.; Ma, X.; Yang, J.; Deng, S.; Wen, Y. Antidiabetic activity of ergosterol from Pleurotus ostreatus in KK-Ay mice with spontaneous type 2 diabetes mellitus. Mol. Nutr. Food Res.2018, 62, 1700444. Google Scholar CrossRef 876. Oei, A.L.; Sweep, F.C.; Thomas, C.M.; Boerman, O.C.; Massuger, L.F. The use of monoclonal antibodies for the treatment of epithelial ovarian cancer. Int. J. Oncol.2008, 32, 1145–1157. Google Scholar CrossRef 877. Pourianezhad, F.; Tahmasebi, S.; Nikfar, S.; Mirhoseini, M.; Abdusi, V. Review on feverfew, a valuable medicinal plant. J. Herbmed Pharmacol.2016, 5. Google Scholar 878. Carlisi, D.; D’Anneo, A.; Angileri, L.; Lauricella, M.; Emanuele, S.; Santulli, A.; Vento, R.; Tesoriere, G. Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J. Cell. Physiol.2011, 226, 1632–1641. Google Scholar CrossRef PubMed 879. Godic, A.; Poljšak, B.; Adamic, M.; Dahmane, R. The role of antioxidants in skin cancer prevention and treatment. Oxid. Med. Cell. Longev.2014, 2014, 860479. Google Scholar CrossRef PubMed 880. Westerlund, A.; Steineck, G.; Bälter, K.; Stattin, P.; Grönberg, H.; Hedelin, M. Dietary supplement use patterns in men with prostate cancer: The Cancer Prostate Sweden study. Ann. Oncol.2011, 22, 967–972. Google Scholar CrossRef PubMed 881. Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and prevention of chronic disease. Crit. Rev. Food Sci. Nutr.2004, 44, 275–295. Google Scholar CrossRef 882. Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med.1994, 330, 1029–1035. Google Scholar CrossRef 883. Goodman, M.; Bostick, R.M.; Kucuk, O.; Jones, D.P. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radic. Biol. Med.2011, 51, 1068–1084. Google Scholar CrossRef 884. Middha, P.; Weinstein, S.J.; Männistö, S.; Albanes, D.; Mondul, A.M. β-carotene supplementation and lung cancer incidence in the alpha-tocopherol, Beta-carotene cancer prevention study: The role of tar and nicotine. Nicotine Tob. Res.2019, 21, 1045–1050. Google Scholar CrossRef Green Version 885. Narita, S.; Saito, E.; Sawada, N.; Shimazu, T.; Yamaji, T.; Iwasaki, M.; Ishihara, J.; Takachi, R.; Shibuya, K.; Inoue, M. Dietary consumption of antioxidant vitamins and subsequent lung cancer risk: The J apan P ublic H ealth C enter-based prospective study. Int. J. Cancer2018, 142, 2441–2460. Google Scholar CrossRef Green Version 886. Klein, E.A.; Thompson, I.M.; Tangen, C.M.; Crowley, J.J.; Lucia, M.S.; Goodman, P.J.; Minasian, L.M.; Ford, L.G.; Parnes, H.L.; Gaziano, J.M. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA2011, 306, 1549–1556. Google Scholar CrossRef 887. Sayin, V.I.; Ibrahim, M.X.; Larsson, E.; Nilsson, J.A.; Lindahl, P.; Bergo, M.O. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med.2014, 6, 221ra15. Google Scholar CrossRef 888. Wiel, C.; Le Gal, K.; Ibrahim, M.X.; Jahangir, C.A.; Kashif, M.; Yao, H.; Ziegler, D.V.; Xu, X.; Ghosh, T.; Mondal, T. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell2019, 178, 330–345. Google Scholar CrossRef PubMed 889. Le Gal, K.; Ibrahim, M.X.; Wiel, C.; Sayin, V.I.; Akula, M.K.; Karlsson, C.; Dalin, M.G.; Akyürek, L.M.; Lindahl, P.; Nilsson, J. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med.2015, 7, 308re8. Google Scholar CrossRef PubMed 890. Vyas, S.; Zaganjor, E.; Haigis, M.C. Mitochondria and cancer. Cell2016, 166, 555–566. Google Scholar CrossRef PubMed 891. Piskounova, E.; Agathocleous, M.; Murphy, M.M.; Hu, Z.; Huddlestun, S.E.; Zhao, Z.; Leitch, A.M.; Johnson, T.M.; DeBerardinis, R.J.; Morrison, S.J. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature2015, 527, 186–191. Google Scholar CrossRef PubMed Green Version 892. Heaney, M.L.; Gardner, J.R.; Karasavvas, N.; Golde, D.W.; Scheinberg, D.A.; Smith, E.A.; O’Connor, O.A. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res.2008, 68, 8031–8038. Google Scholar CrossRef PubMed Green Version 893. Fukui, M.; Yamabe, N.; Zhu, B.T. Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur. J. Cancer2010, 46, 1882–1891. Google Scholar CrossRef PubMed Green Version 894. Li, N.; Sun, C.; Zhou, B.; Xing, H.; Ma, D.; Chen, G.; Weng, D. Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS ONE2014, 9, e100314. Google Scholar CrossRef 895. Wu, Y.J.; Muldoon, L.L.; Neuwelt, E.A. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J. Pharmacol. Exp. Ther.2005, 312, 424–431. Google Scholar CrossRef Green Version

Share and Cite

MDPI and ACS Style Talib, W.H.; Mahmod, A.I.; Abuarab, S.F.; Hasen, E.; Munaim, A.A.; Haif, S.K.; Ayyash, A.M.; Khater, S.; AL-Yasari, I.H.; Kury, L.T.A. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules2021, 26, 2179. https://doi.org/10.3390/molecules26082179

AMA Style Talib WH, Mahmod AI, Abuarab SF, Hasen E, Munaim AA, Haif SK, Ayyash AM, Khater S, AL-Yasari IH, Kury LTA. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules. 2021; 26(8):2179. https://doi.org/10.3390/molecules26082179

Chicago/Turabian Style Talib, Wamidh H., Asma Ismail Mahmod, Sara Feras. Abuarab, Eliza Hasen, Amer A. Munaim, Shatha Khaled Haif, Amani Marwan Ayyash, Samar Khater, Intisar Hadi AL-Yasari, and Lina T. Al Kury. 2021. “Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products” Molecules 26, no. 8: 2179. https://doi.org/10.3390/molecules26082179

Article Metrics

NoNo

Article Access Statistics

For more information on the journal statistics, click here. Multiple requests from the same IP address are counted as one view. MDPI and ACS Style Talib, W.H.; Mahmod, A.I.; Abuarab, S.F.; Hasen, E.; Munaim, A.A.; Haif, S.K.; Ayyash, A.M.; Khater, S.; AL-Yasari, I.H.; Kury, L.T.A. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules2021, 26, 2179. https://doi.org/10.3390/molecules26082179

AMA Style Talib WH, Mahmod AI, Abuarab SF, Hasen E, Munaim AA, Haif SK, Ayyash AM, Khater S, AL-Yasari IH, Kury LTA. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules. 2021; 26(8):2179. https://doi.org/10.3390/molecules26082179

Chicago/Turabian Style Talib, Wamidh H., Asma Ismail Mahmod, Sara Feras. Abuarab, Eliza Hasen, Amer A. Munaim, Shatha Khaled Haif, Amani Marwan Ayyash, Samar Khater, Intisar Hadi AL-Yasari, and Lina T. Al Kury. 2021. “Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products” Molecules 26, no. 8: 2179. https://doi.org/10.3390/molecules26082179

Article Metrics

NoNo

Article Access Statistics

For more information on the journal statistics, click here. Multiple requests from the same IP address are counted as one view. here Multiple requests from the same IP address are counted as one view. Article Processing Charges Pay an Invoice Open Access Policy Contact MDPI Jobs at MDPI For Authors For Reviewers For Editors For Librarians For Publishers For Societies For Conference Organizers Sciforum MDPI Books Preprints.org Scilit SciProfiles Encyclopedia JAMS Proceedings Series LinkedIn Facebook Twitter

wpt global franch

WPT Paris et le WPT Prime Paris 2024 ! Profitez de jeux de poker passionnants et de divertissement au cœur de Paris. Parfait pour tous les fans de poker. Restez à l’écoute pour les nouvelles sur les événements et les offres spéciales !

Ce site ne collecte que des articles connexes. Pour voir l’original, veuillez copier et ouvrir le lien suivant :Diabetes and Cancer: Metabolic Association Therapeutic Challenges and the Role of Natural Products