Review Volume 12, Issue 4 pp 3993—4009

Metformin: current clinical applications in nondiabetic patients with cancer

Figure 1. Possible mechanisms of action of metformin in cancer therapy. Metformin increases the ratio of AMP to ATP by inhibiting mitochondria complex I, activates the adenosine monophosphate activated protein kinase (AMPK) signaling pathway, and represses the insulin-like growth factor-1 receptor (IGF-1R) pathway. Furthermore, AMPK activation decreases the expression level of PD-L1, which allows cytotoxic T-lymphocyte-mediated tumor cell death. Last, metformin could increase the number of CD8+ T tumor-infiltrating lymphocytes. IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IR, insulin receptor; LKB1, liver kinase B1; mTORC1, mammalian target of rapamycin complex 1; OCT, organic cation transporter; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1.