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

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

doi:10.1016/j.ccell.2017.02.018

Back

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

Journal article

Open access

Peer reviewed

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

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, …

Cancer cell, Vol.31(4), pp.487-500.e8

04/10/2017

DOI: 10.1016/j.ccell.2017.02.018

PMCID: PMC6512344

PMID: 28366679

Files and links (1)

url

https://doi.org/10.1016/j.ccell.2017.02.018View

Published (Version of record) Open Access

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. [Display omitted] •High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy•O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity•Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC•Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy Schoenfeld et al. show that cancer cells are selectively sensitive to ascorbate due to their altered redox-active iron metabolism. They present preclinical and clinical data demonstrating the feasibility, tolerability, and potential efficacy of pharmacological ascorbate for treating glioblastoma and non-small cell lung cancer.

Oxidative Stress

non-small cell lung cancer

glioblastoma multiforme

ferritin

labile iron metabolism

superoxide dismutase

hydrogen peroxide

pharmacological ascorbate

transferrin receptor

superoxide

Details

Title: Subtitle: O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate
Creators: Joshua D Schoenfeld - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Zita A Sibenaller - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kranti A Mapuskar - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Brett A Wagner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kimberly L Cramer-Morales - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Muhammad Furqan - 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
Sonia Sandhu - 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
Thomas L Carlisle - 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
Mark C Smith - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Taher Abu Hejleh - 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
Daniel J Berg - 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
Jun Zhang - 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
John Keech - Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kalpaj R Parekh - Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Sudershan Bhatia - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Varun Monga - 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
Kellie L Bodeker - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Logan Ahmann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Sandy Vollstedt - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Heather Brown - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Erin P Shanahan Kauffman - 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
Mary E Schall - 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
Ray J Hohl - 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
Gerald H Clamon - 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
Jeremy D Greenlee - Department of Neurosurgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Matthew A Howard - Department of Neurosurgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Michael K Schultz - Department of Radiology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Brian J Smith - Departmet of Biostatistics, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Dennis P Riley - Galera Therapeutics, Malvern, PA 19355, USA
Frederick E Domann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Joseph J Cullen - Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Garry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
John M Buatti - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Bryan G Allen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cancer cell, Vol.31(4), pp.487-500.e8
DOI: 10.1016/j.ccell.2017.02.018
PMID: 28366679
PMCID: PMC6512344
NLM abbreviation: Cancer Cell
ISSN: 1535-6108
eISSN: 1878-3686
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100001960, name: American Society for Radiation Oncology, award: JF2014-1; name: Carver Research Program of Excellence in Redox Biology; DOI: 10.13039/100000002, name: US NIH, award: R01-CA182804, R01-CA184051, R01-CA169046, U01-CA166800; DOI: 10.13039/100004316, name: IBM; name: CCSG, award: P30-CA086862; name: University of Iowa Medical Scientist Training Program, award: T32-GM007337, T32-CA078586; name: Galera Therapeutics
Language: English
Date published: 04/10/2017
Academic Unit: Neurology; Pathology; Biostatistics; Surgery; Otolaryngology; Radiology; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Radiation Oncology; Neurosurgery; Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9983997454302771

Metrics

45 Record Views

306 Times Cited - Web of Science

See more details

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

Files and links (1)

Related content

Abstract

Details

Metrics