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

• Published in: Cancer cell 2017-04, Vol.31 (4), p.487-500.e8
• Main Authors: Schoenfeld, Joshua D, Sibenaller, Zita A, Mapuskar, Kranti A, Wagner, Brett A, Cramer-Morales, Kimberly L, Furqan, Muhammad, Sandhu, Sonia, Carlisle, Thomas L, Smith, Mark C, Abu Hejleh, Taher, Berg, Daniel J, Zhang, Jun, Keech, John, Parekh, Kalpaj R, Bhatia, Sudershan, Monga, Varun, Bodeker, Kellie L, Ahmann, Logan, Vollstedt, Sandy, Brown, Heather, Shanahan Kauffman, Erin P, Schall, Mary E, Hohl, Ray J, Clamon, Gerald H, Greenlee, Jeremy D, Howard, Matthew A, Schultz, Michael K, Smith, Brian J, Riley, Dennis P, Domann, Frederick E, Cullen, Joseph J, Buettner, Garry R, Buatti, John M, Spitz, Douglas R, Allen, Bryan G
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Ascorbic Acid - administration & dosage; Ascorbic Acid - adverse effects; Ascorbic Acid - pharmacology; Brain Neoplasms - drug therapy; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - radiotherapy; Cell Line, Tumor; Chemoradiotherapy - methods; Female; Glioblastoma - drug therapy; Glioblastoma - metabolism; Humans; Hydrogen Peroxide - pharmacology; Iron - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - radiotherapy; Male; Mice, Nude; Oxygen - metabolism; Radiation-Sensitizing Agents - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.02.018

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 H O ; 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 O and H O 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 H O . In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.