Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer

Wenqing G Sun; Christine J Weydert; Yuping Zhang; Lei Yu; Jingru Liu; Douglas R Spitz; Joseph J Cullen; Larry W Oberley

doi:10.3390/cancers2010068

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Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer

Journal article

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Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer

Wenqing G Sun, Christine J Weydert, Yuping Zhang, Lei Yu, Jingru Liu, Douglas R Spitz, Joseph J Cullen and Larry W Oberley

Cancers, Vol.2(1), pp.68-87

03/2010

DOI: 10.3390/cancers2010068

PMCID: PMC2880814

PMID: 20532186

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Abstract

Overexpression of manganese superoxide dismutase (MnSOD) can sensitize a variety of cancer cell lines to many anticancer drugs. Recent work has shown that cancer cells can be sensitized to cell killing by raising peroxide levels through increased manganese superoxide dismutase (MnSOD) when combined with inhibition of peroxide removal. Here we utilize the mechanistic property of one such anticancer drug, BCNU, which inhibits glutathione reductase (GR), compromising the glutathione peroxidase system thereby inhibiting peroxide removal. The purpose of this study was to determine if anticancer modalities known to produce superoxide radicals can increase the antitumor effect of MnSOD overexpression when combined with BCNU. To enhance MnSOD, an adenoviral construct containing the cDNA for MnSOD (Ad MnSOD ) was introduced into human breast cancer cell line, ZR-75-1. Ad MnSOD infection alone did not alter cell killing, however when GR was inhibited with either BCNU or siRNA, cytotoxicity increased. Futhermore, when the Ad MnSOD + BCNU treatment was combined with agents that enhance steady-state levels of superoxide (TNF-α, antimycin, adriamycin, photosensitizers, and ionizing radiation), both cell cytotoxicity and intracellular peroxide levels increased. These results suggest that the anticancer effect of Ad MnSOD combined with BCNU can be enhanced by agents that increase generation of superoxide.

breast cancer

superoxide

MnSOD

BCNU

hydrogen peroxide

adenovirus

Details

Title: Subtitle: Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer
Creators: Wenqing G Sun - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Christine J Weydert - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Yuping Zhang - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Lei Yu - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Jingru Liu - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Joseph J Cullen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Larry W Oberley - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA; E-Mails
Resource Type: Journal article
Publication Details: Cancers, Vol.2(1), pp.68-87
DOI: 10.3390/cancers2010068
PMID: 20532186
PMCID: PMC2880814
NLM abbreviation: Cancers (Basel)
ISSN: 2072-6694
eISSN: 2072-6694
Publisher: Molecular Diversity Preservation International
Language: English
Date published: 03/2010
Academic Unit: Pathology; Surgery; Radiation Oncology; Obstetrics and Gynecology
Record Identifier: 9984046817902771

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