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#Diabetes and Endocrinology
Metformin, an oral hypoglycemic agent has displayed good safety record in clinical practice over the past few decades. It has also emerged as a potentially beneficial agent for preventing and treating different types of cancers, including prostate cancer. It may exert its anti-cancer effect via two mechanisms: indirect action by lowering systemic insulin levels and direct action on the tumor. The indirect actions of this drug occur through inhibition of hepatic gluconeogenesis. High insulin levels are known to be an adverse prognostic factor for many cancers, like prostate, breast, and colon. Regarding this, metformin has displayed great potential in reducing systemic insulin levels, even in non-diabetic individuals. Reduced circulating insulin subsequently down-regulates the phosphoinositide-3-kinase pathway, which is implicated in growth, proliferation, differentiation, and motility, and is a major factor underlying the growth of prostate cancer.
On the other hand, its direct effectoccurs via inhibition of the mitochondrial electron transport chain and consequent activation of adenosine mono-phosphate-activated protein kinase (AMPK), an energy sensing/signalling protein that is a key control point for maintaining energy homeostasis. When activated, it increases cellular adenosine triphosphate (ATP) by inhibiting anabolic pathways and stimulating catabolic pathways to produce ATP. Activation of AMPK, in turn, causes downstream inhibition of mammalian target of rapamycin complex-1 (mTORC1) signalling, and activation of the tumor suppressor tuberous sclerosis complex 2. mTOR is a key mediator of the phosphatidylinositol-3-kinase/protein kinase B/Akt signalling pathway, one of the pathways commonly deregulated in cancer. Inhibition of mTOR attenuates protein synthesis and tumor cell growth and proliferation. Besides, inhibition of the Krebs cycle may have other direct effects on metabolic pathways like lipid synthesis that contribute significantly to prostate cancer metabolism.
Furthermore, reports have shown lower cancer incidence and cancer-related mortality among diabetics on metformin in comparison to those on other anti-diabetic medications. Information available from some studies have shown advantages of metformin in inhibiting cancer cell proliferation and ameliorating metabolic syndrome in patients with prostate cancer receiving androgen deprivation therapy (ADT). Thus, metformin appears to be a useful adjuvant therapy, especially in patients on ADT. Multiple studies have also demonstrated a beneficial effect of this drug in decreasing the incidence of prostate cancer and improving the overall survival. According to a large population-based study, people who took metformin were approximately 16% less likely to be diagnosed with prostate cancer compared to non-users. There was an inverse relationship between prostate cancer risk and duration, intensity of use, and cumulative dose of metformin. Based on the abovementioned data, it can be suggested that metformin seems to be a promising option for managing prostate cancer.
- Whitburn J, Edwards CM, Sooriakumaran P. Metformin and Prostate Cancer: a New Role for an Old Drug. Curr Urol Rep. 2017;18(6):46.