Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759
Metformin and IACS-010759 are two distinct antimetabolic agents with promising potential in cancer treatment. Metformin, a well-established antidiabetic drug, has a mild inhibitory effect on mitochondrial complex I, while IACS-010759 is a potent inhibitor of the same complex. Mitochondria play a crucial role in cellular energy metabolism by generating adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As such, targeting mitochondrial metabolism and OXPHOS creates a vulnerability in cancer cells. Both drugs have shown encouraging antitumoral effects across various cancers, as evidenced by preclinical in vitro and in vivo studies. This includes direct impacts on cancer cells as well as immunomodulatory effects. While observational epidemiological studies on metformin have been promising, clinical trial results have not met expectations. In contrast, IACS-010759 has demonstrated significant adverse effects, leading to a metabolic shift towards glycolysis and increased lactic acid production. The future of these drugs hinges on further clinical trials for metformin, focusing on prevention, and on understanding the potential toxic effects of IACS-010759 on normal cells.