Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS‐010759

Autor: Marc Pujalte‐Martin, Amine Belaïd, Simon Bost, Michel Kahi, Pascal Peraldi, Matthieu Rouleau, Nathalie M. Mazure, Frédéric Bost
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Molecular Oncology, Vol 18, Iss 7, Pp 1719-1738 (2024)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.13583
Popis: Metformin and IACS‐010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS‐010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS‐01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS‐01075.
Databáze: Directory of Open Access Journals
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