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Figure 2: Antineoplastic mechanisms of action of metformin. The mitochondria are the primary target of metformin. Metformin interferes with oxidative phosphorylation via interactions with respiratory complex I, resulting in reduced ATP production and metabolic stress. Metformin lowers plasma glucose levels by decreasing gluconeogenesis and glucose uptake, resulting in lower circulating insulin and IGF-1 levels. An energy compensation reaction occurring in tumor cells capable of responding to metabolic stress is shown in the left box. By activating the LKB1/AMPK pathway, metformin inhibits mTOR downstream signaling, ultimately causing downregulation of energy-consuming processes and an overall cytostatic effect. The antitumour effects of metformin are regulated by both AMPK-dependent and AMPK-independent mechanisms. If tumor cells lack ability to cope with energetic stress due to the loss of function of LKB1/AMPK or p53, they may undergo a metabolic crisis leading to death (middle box). The right box presents an assumptive mechanism of metformin’s action against CSCs. Both inflammation and the glycolytic phenotype are likely to be associated with pluripotency and stemness. The activation of AMPK provides a metabolic barrier to reprogramming somatic cells into stem cells. Metformin has been demonstrated to inhibit dedifferentiation processes, tumor initiation, and malignant transformation. Anti-inflammatory effects, restoration from glycolysis, and reduced growth signals might explain the anti-CSC action of metformin.