O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Abstract

Summary Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2•− and H2O2 are capable of disrupting intracellular iron metabolism thereby selectively sensitizing non-small cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

A novel red pigment from marineArthrobactersp. G20 with specific anticancer activity

“…In cancerous cells, ROS acts as an apoptosis-promoting agent and the excess of antioxidants can block these cancer-preventive mechanisms and develop cancer (Salganik 2001). Recently Schoenfeld et al (2017), demonstrated that the alterations of redox-active iron metabolisms in cancer cells in comparison to normal cells are responsible for the specific activity of ascorbic acid (antioxidant agent) against nonsmall-cell lung cancer (NSCLC) and glioblastoma (GBM) cells. It is understood from this example that an excess of antioxidants can also kill cancer cells but by using a different mechanism.…”

NADPH oxidase‐derived reactive oxygen species: Dosis facit venenum

“…show positive outcomes if cancer is treated with high concentrations of the antioxidant vitamin C (Schoenfeld et al, 2017).…”

Paradoxical roles of dual oxidases in cancer biology

“…High doses of intravenous vitamin C were found to significantly reduced levels of prostate-specific antigen (PSA), an appreciated serum biomarker for prostate cancer[28]. Pro-oxidant effects of DHA have also been explored in non-small cell lung cancer (NSCLC) and glioblastoma (GBM), where H 2 O 2 induced by the extracellular conversion of ascorbic acid to DHA, selectively disrupted iron metabolism in cancer cells, leading to cytotoxic effects, and its efficacy has been demonstrated in preclinical and clinical trials when paired with standard radiation and chemotherapy regiments[29]. …”