The Mechanism of Action of Biguanides: New Answers to a Complex Question

SIMPLE SUMMARY: In the last two decades, the antidiabetic drugs, biguanides, have received considerable interest owing to their presumed antitumor properties. A critical issue that has been at the center of many studies is how they act at the molecular level. Most works propose that biguanides inhibit mitochondrial complex I, which causes ATP depletion and activation of compensatory responses, responsible for the therapeutic properties. However, complex I can only be inhibited with concentrations of biguanides that cannot be tolerated by animals and patients, suggesting that alternative targets and intracellular perturbations are involved. Here, we will discuss the current knowledge of the mechanisms of action of biguanides, when used under clinically relevant conditions. The ongoing clinical trials in cancer and the proper conditions of usage will also be addressed. Understanding the mode of action of these drugs represents critical information for further investigation and usage in cancer models. ABSTRACT: Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.