Ascorbate Alters Iron Metabolism to Drive Anticancer Toxicity

Vitamin C, also known as ascorbate, is an essential nutrient that exhibits redox functions and inhibits proliferation in various types of solid cancers in vitro, and may enhance the chemosensitivity of patients with ovarian or pancreatic cancer. Although the precise mechanisms underlying cancer cell–selective ascorbate toxicity have not been fully elucidated, recent evidence suggests that ascorbate promotes the production of H₂O₂ in an iron redox–dependent manner, and disruptions in cellular oxidative metabolism increase the levels of reactive oxygen species, such as superoxide (O₂^·-) and H₂O₂, to perturb iron metabolism. Schoenfeld and colleagues evaluated the roles of O₂^·-- and H₂O₂-mediated disruption of iron metabolism in the toxicity of ascorbate against non–small cell lung cancer (NSCLC) and glioblastoma (GBM). Treatment with ascorbate alone or as a radio-chemosensitizer was efficacious against NSCLC and GBM cells, but not normal cells, in vitro and in vivo, and was well tolerated in vivo. Ascorbate toxicity was shown to be independent of dehydroascorbate uptake and dependent on redox-active labile iron and the ascorbate-mediated production of H₂O₂. Similarly, ablation of mitochondrial superoxide dismutase, which catalyzes the dismutation of O₂^·- to either O₂ or H₂O₂, resulted in enhanced ascorbate sensitivity and increased levels of O₂^·-, labile iron, and transferrin receptor, which mediates the intracellular entry of transferrin-bound iron, in NSCLC and GBM cell lines but not in normal cells. Further, catalase-mediated H₂O₂ degradation increased iron–sulfur cluster protein activity whereas ascorbate treatment resulted in decreased iron–sulfur cluster protein activity, suggesting that ascorbate-mediated production of H₂O₂ is responsible for ascorbate-induced increases in labile iron. Phase I/II clinical trials showed that therapeutic doses of ascorbate were well tolerated and enhanced chemotherapy efficacy in patients with NSCLC or radio-chemotherapeutic efficacy in patients with GBM. These results describe the mechanism underlying cancer cell–selective ascorbate-mediated anticancer toxicity and suggest that ascorbate treatment may improve the efficacy of standard-of-care therapy for patients with NSCLC and GBM.

Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, et al. O₂^·-- and H₂O₂-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 2017;31:487–500.e8.