O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.

Abstract

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.

• Authors: Joshua D Schoenfeld, Zita A Sibenaller, Kranti A Mapuskar, Brett A Wagner, Kimberly L Cramer-Morales, Muhammad Furqan, Sonia Sandhu, Thomas L Carlisle, Mark C Smith, Taher Abu Hejleh, Daniel J Berg, Jun Zhang, John Keech, Kalpaj R Parekh, Sudershan Bhatia, Varun Monga, Kellie L Bodeker, Logan Ahmann, Sandy Vollstedt, Heather Brown, Erin P Shanahan Kauffman, Mary E Schall, Ray J Hohl, Gerald H Clamon, Jeremy D Greenlee, Matthew A Howard, Michael K Schultz, Brian J Smith, Dennis P Riley, Frederick E Domann, Joseph J Cullen, Garry R Buettner, John M Buatti, Douglas R Spitz, Bryan G Allen
• Journal: Cancer cell (Cancer Cell) Vol. 31 Issue 4 Pg. 487-500.e8 (04 10 2017) ISSN: 1878-3686 [Electronic] United States
• PMID: 28366679 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Radiation-Sensitizing Agents
• Hydrogen Peroxide
• Iron
• Ascorbic Acid
• Oxygen

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Ascorbic Acid (administration & dosage, adverse effects, pharmacology)
• Brain Neoplasms (drug therapy)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, mortality, radiotherapy)
• Cell Line, Tumor
• Chemoradiotherapy (methods)
• Female
• Glioblastoma (drug therapy, metabolism)
• Humans
• Hydrogen Peroxide (pharmacology)
• Iron (metabolism)
• Lung Neoplasms (drug therapy, metabolism, mortality, radiotherapy)
• Male
• Mice, Nude
• Oxygen (metabolism)
• Radiation-Sensitizing Agents (pharmacology)
• Xenograft Model Antitumor Assays