O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate
Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemoradiotherapy; Female; Glioblastoma; Humans; Hydrogen Peroxide; Iron; Lung Neoplasms; Male; Mice, Nude; Oxygen; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays
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.
Schoenfeld, J., Sibenaller, Z., Mapuskar, K., Wagner, B., Cramer-Morales, K., Furqan, M., Sandhu, S., Carlisle, T., Smith, M., Abu Hejleh, T., Berg, D., Zhang, J., Keech, J., Parekh, K., Bhatia, S., Monga, V., Bodeker, K. L., Ahmann, L., Vollstedt, S., Brown, H., Shanahan Kauffman, E., Schall, M., Hohl, R., Clamon, G., Greenlee, J., Howard, M., Schultz, M., Smith, B., Riley, D., Domann, F., Cullen, J., Buettner, G., Buatti, J., Spitz, D., & Allen, B. (2017). O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer cell, 31 (4). http://dx.doi.org/10.1016/j.ccell.2017.02.018