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

Abstract

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.

Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes

“…Addressing glioblastomas with an oxidative phenotype by targeting specific mitochondrial enzymes and pathways is a promising strategy. The observed upregulation of mitochondrial functions in T98G cells suggests that inhibitors targeting the TCA cycle or oxidative phosphorylation, such as Complex I inhibitors (e.g., IACS-010759), could effectively disrupt their metabolic machinery [ 63 ]. This approach highlights the potential of exploiting the unique metabolic vulnerabilities of glioblastoma cell lines for more effective and personalized therapeutic interventions.…”

Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review

“…While this review primarily focuses on the drug's implications in inflammatory and infectious diseases, it is crucial to acknowledge the wealth of information available on its role in cancer treatment. Interested readers are encouraged to please consult recent publi-cations on metformin's role in cancer, where evidence from epidemiological, pre-clinical, and clinical studies suggests promising implications for cancer prevention in diabetic patients [136][137][138][139]. Limited research has also explored its potential in preventing cancer in non-diabetic animal models, highlighting the need for additional studies to understand its chemopreventive effects in non-diabetics.…”

The Involvement of Ascorbic Acid in Cancer Treatment

“…Additionally, research indicates that elevated doses of VC disrupt glycolysis. They can be combined with the anti-diabetic medication metformin, which also diminishes tumor (acute myelocytic leukemia and other solid tumors) burden through mitochondrial complex I inhibition [68]. A review of recent clinical studies and case analyses suggests that VC, as a co-factor, holds certain potential application value in starvation therapy (Table 2).…”