Overview and critical analysis of clinical trials data and epidemiological surveys proving complex mechanism and controversy of anti-tumorigenic activity of metformin

Abstract

Metformin might influence tumourigenesis throughout AMPK- both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress. Indirectly, metformin exerts its antitumorigenic effects by activating LKB1 (a tumor suppressor protein) and its downstream target AMPK, which, in turn, suppresses the activity of the mammalian target of rapamycin (mTOR), a signaling pathway with a central role in cancer cell growth and cancer pathogenesis. Also it has been shown that AMPK phosphorylates tuberous sclerosis complex-2 (TSC-2) that in turns inhibits mTOR signaling. The induction of energetic stress, that essentially signifies lack of or decrease in available energy resources for the cell, activates AMPK, which results in inhibition of cell growth and proliferation. AMPK activation assists in adaptation to metabolic stress. There have been many clinical trials because of the interest in anti-cancer effects of metformin. In 2014 new research appearing in Proceedings of the National Academy of Sciences, USA suggests that activation of AMPK may actually fuel cancer growth. While meta-analyses of observational studies have shown a reduced risk of cancer among patients on metformin, a similar analysis of randomized controlled trials, lately found no relationship between metformin and cancer risk. A retrospective cohort study, investigating the association between use of metformin compared with other antidiabetes medications, proves that Metformin does not affect cancer risk.