A selenium‐iron axis dictates cancer cell sensitivity to pharmacologic ascorbate

Abstract

High‐dose ascorbate (vitamin C) has shown promising anti‐cancer activity. We sought to distinguish the mechanism of cancer cell ascorbate toxicity between two proposed models: hydrogen peroxide (H2O2) generation by ascorbate itself or glutathione depletion by its oxidized form, dehydroascorbate. Using a combination of metabolic and genetic approaches, we show that ascorbate kills cancer cells through a free radical mechanism that is promoted by iron and suppressed by selenium. High‐dose ascorbate’s metabolic effects and cytotoxicity result from hydrogen peroxide independent of dehydroascorbate. Cytotoxicity further depends on iron via a route distinct from canonical ferroptosis, as the hydrogen peroxide‐detoxifying selenoenzyme GPX1 is critical while the ferroptosis‐suppressing GPX4 is dispensable. Selenium‐mediated protection from ascorbate is powered by NADPH from the pentose phosphate pathway. In a mouse model of glioblastoma, dietary selenium deprivation enhances the efficacy of ascorbate as an anti‐cancer agent. These data establish iron and selenium as opposing mediators of high‐dose ascorbate’s pharmacological activity. More generally, they suggest that cancer sensitivity to free‐radical therapies depends on mineral bioavailability.