Limits...
Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA - J Cancer (2014)

Bottom Line: Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors.In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes.We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha - Qatar;

ABSTRACT
Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

No MeSH data available.


Related in: MedlinePlus

Metformin transporters: Isoforms and genes that demonstrate a role in metformin pharmacokinetics, pharmacogenetics, and thus have an impact on its pharmacological efficacy. Metformin is absorbed from the lumen of the gastrointestinal tract through plasma membrane monoamine transporter (PMAT). It requires the organic cation transporters (OCTs), located in the basolateral membrane of human hepatocytes, to be transported into the liver, thus decreasing hepatic glucose synthesis. The multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2), located in the apical membrane of kidney proximal tubular cells, facilitate metformin excretion into urine. Genetic variation in transporter genes may alter transporter expression and functionality and thus metformin response.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4216797&req=5

Figure 2: Metformin transporters: Isoforms and genes that demonstrate a role in metformin pharmacokinetics, pharmacogenetics, and thus have an impact on its pharmacological efficacy. Metformin is absorbed from the lumen of the gastrointestinal tract through plasma membrane monoamine transporter (PMAT). It requires the organic cation transporters (OCTs), located in the basolateral membrane of human hepatocytes, to be transported into the liver, thus decreasing hepatic glucose synthesis. The multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2), located in the apical membrane of kidney proximal tubular cells, facilitate metformin excretion into urine. Genetic variation in transporter genes may alter transporter expression and functionality and thus metformin response.

Mentions: Information on the pharmacological response to metformin requires an understanding of both its pharmacokinetics and genetic variation of the different transporters for the di-directional movement of metformin across plasma membranes 17 (Fig.2). Metformin is absorbed from the lumen of the gastrointestinal tract (GI) through plasma membrane monoamine transporter (PMAT, or equilibrative nucleoside transporter-ENT-4) 18. By its passage through the organic cation transporter 1 (OCT1), located in the basolateral membrane of human hepatocytes, metformin decreases hepatic glucose synthesis 19. Indeed, this was confirmed by investigations on OCT1 gene-deficient mice, where the uptake of metformin in hepatic and intestinal tissues was lower, compared to control animals 19. These studies implied that OCT1 is pivotal for raising the intracellular concentration of metformin; and as a corollary, there was a corresponding derangement in glucose metabolism 19. Interestingly, metformin is excreted unmetabolized through mutli-drug and toxin extrusion 1 (MATE1) and MATE2, located in the apical membrane of kidney proximal tubular cells, into urine 20. Recent studies suggest that substantial inter-individual heterogeneity in metformin pharmacokinetics exists, and this is recognized to be due to genetic variants of different metformin transporter proteins 20-22. Reduced expression or altered functionality of transporter proteins will result in less than optimum pharmacotherapy or undesirable toxic effects of metformin.


Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA - J Cancer (2014)

Metformin transporters: Isoforms and genes that demonstrate a role in metformin pharmacokinetics, pharmacogenetics, and thus have an impact on its pharmacological efficacy. Metformin is absorbed from the lumen of the gastrointestinal tract through plasma membrane monoamine transporter (PMAT). It requires the organic cation transporters (OCTs), located in the basolateral membrane of human hepatocytes, to be transported into the liver, thus decreasing hepatic glucose synthesis. The multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2), located in the apical membrane of kidney proximal tubular cells, facilitate metformin excretion into urine. Genetic variation in transporter genes may alter transporter expression and functionality and thus metformin response.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216797&req=5

Figure 2: Metformin transporters: Isoforms and genes that demonstrate a role in metformin pharmacokinetics, pharmacogenetics, and thus have an impact on its pharmacological efficacy. Metformin is absorbed from the lumen of the gastrointestinal tract through plasma membrane monoamine transporter (PMAT). It requires the organic cation transporters (OCTs), located in the basolateral membrane of human hepatocytes, to be transported into the liver, thus decreasing hepatic glucose synthesis. The multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2), located in the apical membrane of kidney proximal tubular cells, facilitate metformin excretion into urine. Genetic variation in transporter genes may alter transporter expression and functionality and thus metformin response.
Mentions: Information on the pharmacological response to metformin requires an understanding of both its pharmacokinetics and genetic variation of the different transporters for the di-directional movement of metformin across plasma membranes 17 (Fig.2). Metformin is absorbed from the lumen of the gastrointestinal tract (GI) through plasma membrane monoamine transporter (PMAT, or equilibrative nucleoside transporter-ENT-4) 18. By its passage through the organic cation transporter 1 (OCT1), located in the basolateral membrane of human hepatocytes, metformin decreases hepatic glucose synthesis 19. Indeed, this was confirmed by investigations on OCT1 gene-deficient mice, where the uptake of metformin in hepatic and intestinal tissues was lower, compared to control animals 19. These studies implied that OCT1 is pivotal for raising the intracellular concentration of metformin; and as a corollary, there was a corresponding derangement in glucose metabolism 19. Interestingly, metformin is excreted unmetabolized through mutli-drug and toxin extrusion 1 (MATE1) and MATE2, located in the apical membrane of kidney proximal tubular cells, into urine 20. Recent studies suggest that substantial inter-individual heterogeneity in metformin pharmacokinetics exists, and this is recognized to be due to genetic variants of different metformin transporter proteins 20-22. Reduced expression or altered functionality of transporter proteins will result in less than optimum pharmacotherapy or undesirable toxic effects of metformin.

Bottom Line: Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors.In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes.We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha - Qatar;

ABSTRACT
Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

No MeSH data available.


Related in: MedlinePlus