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

by Selleckchem | Aug 23 2023

MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In 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 high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.

Comments:

The passage you provided highlights the role of MYC as an oncogenic driver in multiple tumor types and discusses how this characteristic can be exploited for targeted pharmacological intervention. Specifically, the passage mentions that drugs suppressing mitochondrial respiration selectively kill cells that overexpress MYC, suggesting a potential vulnerability that can be targeted for therapeutic purposes.

The authors of the passage describe their study in which they investigate the mechanistic basis for the synthetic lethal interaction between MYC overexpression and mitochondrial respiration inhibition. They focus on a specific inhibitor of respiratory complex I called IACS-010759. In a B-lymphoid cell line, the researchers found that ectopic MYC activity, along with treatment using IACS-010759, led to oxidative stress. This stress caused a depletion of reduced glutathione and disrupted redox homeostasis, ultimately resulting in cell death.

To enhance the anticancer effects of IACS-010759, the researchers explored additional strategies. They found that inhibiting the production of NADPH through the pentose phosphate pathway or using high-dose ascorbate (vitamin C), which can act as a pro-oxidant, further increased the efficacy of IACS-010759 in killing MYC-overexpressing cells in vitro. Additionally, this combination of complex I inhibition and high-dose ascorbate improved the therapeutic action of IACS-010759 against human B-cell lymphoma xenografts in mice.

Based on their findings, the authors suggest that the combination of complex I inhibition (using IACS-010759) and high-dose ascorbate could potentially be a promising approach to improve the treatment outcome for patients with high-grade lymphomas and other cancers driven by MYC.