Ascorbate disrupts iron metabolism to cause H2O2-mediated oxidative damage to NSCLC and GBM.

  • Major finding: Ascorbate disrupts iron metabolism to cause H2O2-mediated oxidative damage to NSCLC and GBM.

  • Mechanism: Ascorbate-mediated increases of mitochondrial O2·- and H2O2 expand the redox-active labile iron pool.

  • Impact: Targeting tumor oxidative metabolism with ascorbate may be an efficacious anticancer therapy.

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.