Metformin, an oral biguanide used for first-line treatment of type 2 diabetes mellitus, has attracted attention for its anti-proliferative and anti-cancer effects in several solid tumors, including prostate cancer (PCa). Liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) activation, inhibition of the mammalian target of rapamycin (mTOR) activity and protein synthesis, induction of apoptosis and autophagy by p53 and p21, and decreased blood insulin level have been suggested as direct anti-cancer mechanisms of metformin. Research has shown that PCa development and progression are associated with metabolic syndrome and its components. Therefore, reduction in the risk of PCa and improvement in survival in metformin users may be the results of the direct anti-cancer mechanisms of the drug or the secondary effects from improvement of metabolic syndrome. In contrast, some research has suggested that there is no association between metformin use and PCa incidence or survival. In this comprehensive review, we summarize updated evidence on the relationship between metformin use and oncological effects in patients with PCa. We also highlight ongoing clinical trials evaluating metformin as an adjuvant therapy in novel drug combinations in various disease settings.
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