Molecular mechanisms underlining the role of metformin as a therapeutic agent in lung cancer.

Abstract

Metformin, a first-line therapeutic for type 2 diabetes, has been studied for its potential use in cancer treatment following a number of epidemiological studies that have demonstrated reduced cancer incidence and mortality rates among patients treated with the drug. As yet, however, there remains significant uncertainty about the molecular mechanisms by which metformin exerts its anti-cancer effects. Herein, we summarize the evidence surrounding the anti-lung cancer effects of metformin. Specifically, we explore protein targets of metformin, including AMPK, PP2A, IRF-1/YAP and HGF and we outline the proposed mechanisms of action for metformin in lung cancer, with particular attention given to apoptosis and autophagy. We also closely examine the synergistic activity of metformin with existing cancer treatment regimens, such as TKI's, platinum-based agents and immune therapeutics. In addition to considering preclinical and clinical studies, we also dissect and contextualize the limitations and inconsistencies of the current literature, especially those of epidemiological studies. Finally, we offer a potential trajectory for future research in this rapidly evolving area of basic and clinical oncology.