Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR Signaling Pathways

Abstract

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Further, various studies have confirmed the inhibitory effects of MET on cancer cell lines’ propagation, migration, and invasion. However, despite the many publications on the anticancer potential of MET, there is no existing comprehensive review and account of its autophagy-associated anticancer activity, this review. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5′ adenosine monophosphate-activated protein kinase (AMPK), thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. Therefore, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.