Metformin in Cancer : Chemical Pathways for Tumoral Control Independent of Amp-Dependent Kinase

Dimethylbiguanide (Metformin) is an anti-hyperglycemic drug used in the management of insulin resistance-related diseases like type 2 diabetes mellitus for over 40 years. The molecular mechanisms of action related to its metabolic effects are linked to dependent and independent AMP-dependent kinase (AMPK) activation. Epidemiological evidence has suggested that metformin administration has been associated to lower cancer risk and cancer-related mortality in patients with type 2 diabetes mellitus. Anti-tumoral properties have been described via AMPK-dependent and independent pathways. Metformin is a cationic molecule capable of copper sequestration and subsequent mitochondrial electron transport inhibition, compromising oxidative phosphorylation. Moreover, metformin has also been confirmed to modulate pluripotency in cancer stem cells, blunting their survival and proliferation. Finally, the reduction of vitamin B12 availability has also been suggested to control onecarbon metabolism, DNA synthesis and cytostatic effects. The purpose of this review is to examine the AMPK-independent related mechanisms concerning tumor expansion control and survival. Special Issue on Antidiabetic DrugMetformin