Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism
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 GS...
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| Veröffentlicht in: | Radiation research 2016-10, Vol.186 (4), p.385-395 |
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| creator | Rodman, Samuel N. Spence, Jacquelyn M. Ronnfeldt, Tyler J. Zhu, Yueming Solst, Shane R. O'Neill, Rebecca A. Allen, Bryan G. Guan, Xiangming Spitz, Douglas R. Fath, Melissa A. |
| description | 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 xc– 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. |
| doi_str_mv | 10.1667/RR14463.1 |
| format | Article |
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The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc– 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.</description><identifier>ISSN: 0033-7587</identifier><identifier>EISSN: 1938-5404</identifier><identifier>DOI: 10.1667/RR14463.1</identifier><identifier>PMID: 27643875</identifier><language>eng</language><publisher>United States: The Radiation Research Society</publisher><subject>Acetylcysteine - analogs & derivatives ; Acetylcysteine - pharmacology ; Animals ; Auranofin - pharmacology ; Breast cancer ; Breast Neoplasms - pathology ; Buthionine Sulfoximine - pharmacology ; Cell Line, Tumor ; Cell Movement - drug effects ; Cell Movement - radiation effects ; Cell Survival - drug effects ; Cell Survival - radiation effects ; Cell Transformation, Neoplastic ; DNA Damage ; Drug Interactions ; Female ; Glutathione - biosynthesis ; Glutathione - metabolism ; Humans ; Irradiation ; Mice ; Neoplasm Invasiveness ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Neoplastic Stem Cells - radiation effects ; Oxidative stress ; Pancreatic cancer ; Radiation-Sensitizing Agents - pharmacology ; REGULAR ARTICLES ; Stem cells ; Sulfasalazine - pharmacology ; Survival Analysis ; Thiocarbamates - pharmacology ; Thioredoxin-Disulfide Reductase - antagonists & inhibitors ; Thioredoxins - metabolism</subject><ispartof>Radiation research, 2016-10, Vol.186 (4), p.385-395</ispartof><rights>2016 by Radiation Research Society</rights><rights>Copyright © 2016 Radiation Research Society</rights><rights>Copyright Allen Press Publishing Services Oct 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b490t-97fd86b7d273e57fcef24a0edd1b1a7108a1d21283e61da460dff241502a5fdc3</citedby><cites>FETCH-LOGICAL-b490t-97fd86b7d273e57fcef24a0edd1b1a7108a1d21283e61da460dff241502a5fdc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26427942$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26427942$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,780,784,803,885,27924,27925,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27643875$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rodman, Samuel N.</creatorcontrib><creatorcontrib>Spence, Jacquelyn M.</creatorcontrib><creatorcontrib>Ronnfeldt, Tyler J.</creatorcontrib><creatorcontrib>Zhu, Yueming</creatorcontrib><creatorcontrib>Solst, Shane R.</creatorcontrib><creatorcontrib>O'Neill, Rebecca A.</creatorcontrib><creatorcontrib>Allen, Bryan G.</creatorcontrib><creatorcontrib>Guan, Xiangming</creatorcontrib><creatorcontrib>Spitz, Douglas R.</creatorcontrib><creatorcontrib>Fath, Melissa A.</creatorcontrib><title>Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism</title><title>Radiation research</title><addtitle>Radiat Res</addtitle><description>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 xc– 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.</description><subject>Acetylcysteine - analogs & derivatives</subject><subject>Acetylcysteine - pharmacology</subject><subject>Animals</subject><subject>Auranofin - pharmacology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - pathology</subject><subject>Buthionine Sulfoximine - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - radiation effects</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - radiation effects</subject><subject>Cell Transformation, Neoplastic</subject><subject>DNA Damage</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>Glutathione - biosynthesis</subject><subject>Glutathione - metabolism</subject><subject>Humans</subject><subject>Irradiation</subject><subject>Mice</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Neoplastic Stem Cells - radiation effects</subject><subject>Oxidative stress</subject><subject>Pancreatic cancer</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>REGULAR ARTICLES</subject><subject>Stem cells</subject><subject>Sulfasalazine - pharmacology</subject><subject>Survival Analysis</subject><subject>Thiocarbamates - pharmacology</subject><subject>Thioredoxin-Disulfide Reductase - antagonists & inhibitors</subject><subject>Thioredoxins - 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A.</au><au>Allen, Bryan G.</au><au>Guan, Xiangming</au><au>Spitz, Douglas R.</au><au>Fath, Melissa A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism</atitle><jtitle>Radiation research</jtitle><addtitle>Radiat Res</addtitle><date>2016-10-01</date><risdate>2016</risdate><volume>186</volume><issue>4</issue><spage>385</spage><epage>395</epage><pages>385-395</pages><issn>0033-7587</issn><eissn>1938-5404</eissn><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 xc– 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.</abstract><cop>United States</cop><pub>The Radiation Research Society</pub><pmid>27643875</pmid><doi>10.1667/RR14463.1</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Radiation research, 2016-10, Vol.186 (4), p.385-395 |
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| subjects | Acetylcysteine - analogs & derivatives Acetylcysteine - pharmacology Animals Auranofin - pharmacology Breast cancer Breast Neoplasms - pathology Buthionine Sulfoximine - pharmacology Cell Line, Tumor Cell Movement - drug effects Cell Movement - radiation effects Cell Survival - drug effects Cell Survival - radiation effects Cell Transformation, Neoplastic DNA Damage Drug Interactions Female Glutathione - biosynthesis Glutathione - metabolism Humans Irradiation Mice Neoplasm Invasiveness Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Neoplastic Stem Cells - radiation effects Oxidative stress Pancreatic cancer Radiation-Sensitizing Agents - pharmacology REGULAR ARTICLES Stem cells Sulfasalazine - pharmacology Survival Analysis Thiocarbamates - pharmacology Thioredoxin-Disulfide Reductase - antagonists & inhibitors Thioredoxins - metabolism |
| title | Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism |
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