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Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30.

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

Author information

1
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
2
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.
3
Department of Surgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
4
Department of Neurosurgery, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
5
Department of Radiology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
6
Departmet of Biostatistics, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
7
Galera Therapeutics, Malvern, PA 19355, USA.
8
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.
9
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.

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.

KEYWORDS:

ferritin; glioblastoma multiforme; hydrogen peroxide; labile iron metabolism; non-small cell lung cancer; oxidative stress; pharmacological ascorbate; superoxide; superoxide dismutase; transferrin receptor

Comment in

PMID:
28366679
PMCID:
PMC5497844
DOI:
10.1016/j.ccell.2017.02.018
[Indexed for MEDLINE]
Free PMC Article

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