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 H2O2are 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.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schoenfeld
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kranti A
authors.initials: KA
authors.lastname: Mapuskar
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Cramer-Morales
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Furqan
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Carlisle
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Smith
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Taher
authors.initials: T
authors.lastname: Abu Hejleh
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Berg
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: John
authors.initials: J
authors.lastname: Keech
authors.affiliation: Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kalpaj R
authors.initials: KR
authors.lastname: Parekh
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sudershan
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Monga
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kellie L
authors.initials: KL
authors.lastname: Bodeker
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Ahmann
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Vollstedt
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Brown
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Shanahan Kauffman
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Schall
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ray J
authors.initials: RJ
authors.lastname: Hohl
authors.affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Clamon
authors.affiliation: Department of Neurosurgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Greenlee
authors.affiliation: Department of Neurosurgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Howard
authors.affiliation: Department of Radiology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schultz
authors.affiliation: Departmet of Biostatistics, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: Galera Therapeutics, Malvern, PA 19355, USA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Riley
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
authors.affiliation: Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cullen
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Buatti
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA. Electronic address: douglas-spitz@uiowa.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA. Electronic address: bryan-allen@uiowa.edu.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Allen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D008297:Male; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid; D010100:Oxygen
keywords: ferritin; glioblastoma multiforme; hydrogen peroxide; labile iron metabolism; non-small cell lung cancer; oxidative stress; pharmacological ascorbate; superoxide; superoxide dismutase; transferrin receptor