Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma

MYC is really a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a number of vulnerabilities that offer possibilities for targeted medicinal intervention. For instance, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we solve the mechanistic grounds for this synthetic lethal interaction and exploit it to enhance the anticancer results of the respiratory system complex I inhibitor IACS-010759. Inside a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added as much as induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect might be enhanced either with inhibitors of NADPH production with the pentose phosphate path, or with ascorbate (ascorbic acid), recognized to behave as a professional-oxidant at high doses. During these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and-dose ascorbate might enhance the results of patients impacted by high-grade lymphomas and potentially other MYC-driven cancers.