Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways.

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. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate‐activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. 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′ 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. In summary, 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. Significance statement: This comprehensive review article explores the potential of metformin (MET) as an anticancer agent, focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. MET has shown potential as an anticancer agent by regulating key signaling pathways such as PI3K, LC3‐I and LC3‐II, Beclin‐1, p53, and the autophagy‐related gene (ATG), inhibiting the mammalian target of rapamycin (mTOR) protein, downregulating the expression of p62/SQSTM1, and blocking the cell cycle at the G0/G1 phase. The ability of MET to stimulate autophagy through the AMPK pathway presents a potential strategy for inhibiting the development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non‐small cell lung cancer. The detailed review of MET's effects on cancer in experimental and clinical studies, with a focus on autophagy and the AMPK/mTOR signaling pathways, provides a framework for future investigations and the potential repurposing of MET for cancer treatment. This signifies the importance of exploring MET's role in cancer therapy and its implications for clinical practice. [ABSTRACT FROM AUTHOR]