@article{0d96222a47cf4d7d82236c44255e5818,
title = "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.",
author = "Schoenfeld, {Joshua D.} and Sibenaller, {Zita A.} and Mapuskar, {Kranti A.} and Wagner, {Brett A.} and Cramer-Morales, {Kimberly L.} and Muhammad Furqan and Sonia Sandhu and Carlisle, {Thomas L.} and Smith, {Mark C.} and {Abu Hejleh}, Taher and Berg, {Daniel J.} and Jun Zhang and John Keech and Parekh, {Kalpaj R.} and Sudershan Bhatia and Varun Monga and Bodeker, {Kellie L.} and Logan Ahmann and Sandy Vollstedt and Heather Brown and {Shanahan Kauffman}, {Erin P.} and Schall, {Mary E.} and Hohl, {Ray J.} and Clamon, {Gerald H.} and Greenlee, {Jeremy D.} and Howard, {Matthew A.} and Shultz, {Michael K.} and Smith, {Brian J.} and Riley, {Dennis P.} and Domann, {Frederick E.} and Cullen, {Joseph J.} and Buettner, {Garry R.} and Buatti, {John M.} and Spitz, {Douglas R.} and Allen, {Bryan G.}",
note = "Funding Information: The authors thank Rita Sigmund, Joseph Galbraith, Dr. Michael Knudson, and Dr. Robert Robinson from The University of Iowa (UI) Tissue Procurement Core. The authors also acknowledge Dr. Michael McCormick and Amanda Kalen from the UI Radiation and Free Radical Research Core for performing SOD activity assays and irradiation services, respectively. All flow cytometry data presented herein were obtained at the UI Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran's Administration Medical Center. We would also like to thank Dr. James Martin for allowing us to utilize his confocal microscope. We would also like to thank Dr. Paul Akhenblit for his help with the resazurin metabolic activity studies. Finally, the authors would like to thank Claire Doskey for thoughtful discussion throughout the studies and Gareth Smith for graphical design assistance. This work is supported by American Society for Radiation Oncology (ASTRO) grant JF2014-1 (to B.G.A.), the Carver Research Program of Excellence in Redox Biology (to D.R.S.), and US NIH grants R01-CA182804 (to D.R.S.), R01-CA184051 (to J.J.C.), R01-CA169046 (to G.R.B.), U01-CA166800 (to J.M.B.), a gift from Ms. Marie Foster/matched by IBM, and CCSG P30-CA086862 to The University of Iowa Holden Comprehensive Cancer Center. J.D.S. was supported by T32-GM007337 (to the University of Iowa Medical Scientist Training Program), and J.D.S. and K.L.C.-M. were supported by T32-CA078586 (to D.R.S.). Dr. Dennis Riley is the Chief Scientific Officer of Galera Therapeutics, which supplied GC4419 SOD mimetic for use in these studies. J.M.B., D.R.S., and B.G.A. have sponsored research agreements with Galera Therapeutics for unrelated projects. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = apr,
day = "10",
doi = "10.1016/j.ccell.2017.02.018",
language = "English (US)",
volume = "31",
pages = "487--500.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}