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- W4384696524 abstract "Abstract Cancer cells are highly reliant on bioenergetic processes to support their growth and survival. Disrupting these metabolic pathways, notably by targeting the electron transport chain complexes (ETC-I to V) in the mitochondrial bioenergetic hub, has become an attractive therapeutic strategy. As a result, the pursuit of identifying clinically effective new inhibitors of the respiratory chain with minimized adverse effects stands as a significant objective. Here, we characterize a first in class OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and decoupling effect. MS-L6 is effective on both intact and fragmented mitochondrial membranes, indicating that its efficacy does not rely on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines, while having minimal effects on primary hepatocytes. Its dose-dependently inhibits cell proliferation or induces cell death in a wide range of cancer cell lines, including B-cell and T-cell lymphoma, as well as pediatric sarcoma. Furthermore, ectopic expression of Saccharomyces cerevisiae NADH-dehydrogenase NDI1 partially restores the viability of lymphoma B cells treated with MS-L6, demonstrating that inhibition of NADH oxidation is key for its antitumoral activity. Finally, MS-L6 administration induces a robust inhibition of lymphoma tumor growth in two murine xenograft models, without significant toxicity. Therefore, our data unveil MS-L6 as an inhibitor of oxidative phosphorylation (OXPHOS), with an unexpected dual mechanism of action on the respiratory chain. Additionally, MS-L6 demonstrates potent antitumoral properties in preclinical models, positioning it as the pioneering member of a promising new drug class to be assessed for cancer therapy." @default.
- W4384696524 created "2023-07-20" @default.
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- W4384696524 date "2023-07-18" @default.
- W4384696524 modified "2023-10-17" @default.
- W4384696524 title "A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity" @default.
- W4384696524 doi "https://doi.org/10.21203/rs.3.rs-3144730/v1" @default.
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