Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism

Samuel N Rodman; Jacquelyn M Spence; Tyler J Ronnfeldt; Yueming Zhu; Shane R Solst; Rebecca A O'Neill; Bryan G Allen; Xiangming Guan; Douglas R Spitz; Melissa A Fath

doi:10.1667/RR14463.1

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Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism

Journal article

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Peer reviewed

Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism

Samuel N Rodman, Jacquelyn M Spence, Tyler J Ronnfeldt, Yueming Zhu, Shane R Solst, Rebecca A O'Neill, Bryan G Allen, Xiangming Guan, Douglas R Spitz and Melissa A Fath

Radiation research, Vol.186(4), pp.385-395

10/2016

DOI: 10.1667/RR14463.1

PMCID: PMC5077643

PMID: 27643875

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Abstract

The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of x cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44 CD24 ESA or ALDH1) and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations. Combined inhibition of GSH and Trx metabolism enhanced cancer cell clonogenic killing and radiation responses in human breast and pancreatic cancer cells via a mechanism that could be inhibited by N-acetylcysteine (NAC). Au, BSO and radiation also significantly decreased breast cancer cell migration and invasion in a thiol-dependent manner that could be inhibited by NAC. In addition, pretreating cells with Au sensitized breast cancer stem cell populations to radiation in vitro as determined by CD44 CD24 ESA or ALDH1. Combined administration of Au and BSO, given prior to irradiation, significantly increased the survival of mice with human breast cancer xenografts, and decreased the number of ALDH1 cancer stem cells. These results indicate that combined inhibition of GSH- and Trx-dependent thiol metabolism using pharmacologically relevant agents can enhance responses of human breast cancer stem cells to radiation both in vitro and in vivo.

Buthionine Sulfoximine - pharmacology

Glutathione - metabolism

Neoplastic Stem Cells - drug effects

Humans

Sulfasalazine - pharmacology

Glutathione - biosynthesis

Drug Interactions

Thiocarbamates - pharmacology

Neoplastic Stem Cells - metabolism

Acetylcysteine - analogs & derivatives

Neoplastic Stem Cells - pathology

Female

Thioredoxins - metabolism

Neoplastic Stem Cells - radiation effects

Auranofin - pharmacology

Cell Survival - drug effects

Neoplasm Invasiveness

Radiation-Sensitizing Agents - pharmacology

Cell Survival - radiation effects

Cell Movement - radiation effects

Cell Movement - drug effects

Animals

Breast Neoplasms - pathology

Cell Transformation, Neoplastic

Acetylcysteine - pharmacology

Survival Analysis

Cell Line, Tumor

Mice

Thioredoxin-Disulfide Reductase - antagonists & inhibitors

DNA Damage

Details

Title: Subtitle: Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism
Creators: Samuel N Rodman - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Jacquelyn M Spence - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Tyler J Ronnfeldt - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Yueming Zhu - b Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and
Shane R Solst - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Rebecca A O'Neill - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Bryan G Allen - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Xiangming Guan - c Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota 57007
Douglas R Spitz - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Melissa A Fath - a Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240
Resource Type: Journal article
Publication Details: Radiation research, Vol.186(4), pp.385-395
DOI: 10.1667/RR14463.1
PMID: 27643875
PMCID: PMC5077643
NLM abbreviation: Radiat Res
ISSN: 0033-7587
eISSN: 1938-5404
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS P30 CA086862 / NCI NIH HHS R01 CA182804 / NCI NIH HHS
Language: English
Date published: 10/2016
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984047765702771

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