Biguanides exert antitumor activities through various biochemical mechanisms involving mitochondrial complex I, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and/or mitochondrial glycerophosphate dehydrogenase (mGPD).
Biguanides selectively target subpopulations of cancer cells addicted to oxidative phosphorylation (OXPHOS).
Metabolic adaptations triggered by biguanide exposure could be potential targets to improve the antitumor efficacy of biguanides.
Biguanides modulate antitumor immunity by targeting immune cells in the tumor microenvironment.
Numerous clinical trials are ongoing to evaluate the efficacy of biguanides for the treatment of cancer, especially in combination with targeted and immune therapies.
Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment.
However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent