The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity
Summary The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s action in several cancer and normal cells tr...
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| Veröffentlicht in: | Investigational new drugs 2012-02, Vol.30 (1), p.130-143 |
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| creator | Tarasenko, Nataly Kessler-Icekson, Gania Boer, Pnina Inbal, Aida Schlesinger, Hadassa Phillips, Don R. Cutts, Suzanne M. Nudelman, Abraham Rephaeli, Ada |
| description | Summary
The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use. |
| doi_str_mv | 10.1007/s10637-010-9542-z |
| format | Article |
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The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-010-9542-z</identifier><identifier>PMID: 20862515</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Angiogenesis ; Angiogenic Proteins - metabolism ; Animals ; Antibodies ; Antibodies - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - toxicity ; Apoptosis ; Astrocytes - drug effects ; Astrocytes - pathology ; Brain Neoplasms - enzymology ; Brain Neoplasms - pathology ; Breast cancer ; Breast Neoplasms - enzymology ; Breast Neoplasms - immunology ; Breast Neoplasms - pathology ; Butyrates - pharmacology ; Cardiomyocytes ; Cardiotoxicity ; Cell Line, Tumor ; Cell Survival - drug effects ; Cells ; Cytoprotection ; Cytotoxicity ; Dose-Response Relationship, Drug ; Doxorubicin - pharmacology ; Drug dosages ; Drug Synergism ; Female ; Fibroblasts - drug effects ; Fibroblasts - pathology ; Gene expression ; Glioblastoma - enzymology ; Glioblastoma - pathology ; Growth factors ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Inflammation Mediators - metabolism ; Inhibitor drugs ; Inhibitory Concentration 50 ; Laboratory animals ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - pathology ; Oncology ; Organophosphorus Compounds - pharmacology ; Pharmacology ; Pharmacology/Toxicology ; Preclinical Studies ; Proteins ; Rats ; Reactive Oxygen Species - metabolism ; Receptor, ErbB-2 - immunology ; Studies ; Testing laboratories ; Time Factors ; Toxicity ; Tumor necrosis factor-TNF</subject><ispartof>Investigational new drugs, 2012-02, Vol.30 (1), p.130-143</ispartof><rights>Springer Science+Business Media, LLC 2010</rights><rights>Springer Science+Business Media, LLC 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-3676c1cba03c8e28f54da66623dfe04c60eeb556b979353e78855e1a402b2a7b3</citedby><cites>FETCH-LOGICAL-c404t-3676c1cba03c8e28f54da66623dfe04c60eeb556b979353e78855e1a402b2a7b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-010-9542-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-010-9542-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20862515$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tarasenko, Nataly</creatorcontrib><creatorcontrib>Kessler-Icekson, Gania</creatorcontrib><creatorcontrib>Boer, Pnina</creatorcontrib><creatorcontrib>Inbal, Aida</creatorcontrib><creatorcontrib>Schlesinger, Hadassa</creatorcontrib><creatorcontrib>Phillips, Don R.</creatorcontrib><creatorcontrib>Cutts, Suzanne M.</creatorcontrib><creatorcontrib>Nudelman, Abraham</creatorcontrib><creatorcontrib>Rephaeli, Ada</creatorcontrib><title>The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.</description><subject>Angiogenesis</subject><subject>Angiogenic Proteins - metabolism</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - toxicity</subject><subject>Apoptosis</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - pathology</subject><subject>Brain Neoplasms - enzymology</subject><subject>Brain Neoplasms - pathology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - enzymology</subject><subject>Breast Neoplasms - immunology</subject><subject>Breast Neoplasms - pathology</subject><subject>Butyrates - pharmacology</subject><subject>Cardiomyocytes</subject><subject>Cardiotoxicity</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Cells</subject><subject>Cytoprotection</subject><subject>Cytotoxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug dosages</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - pathology</subject><subject>Gene expression</subject><subject>Glioblastoma - enzymology</subject><subject>Glioblastoma - pathology</subject><subject>Growth factors</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Inflammation Mediators - metabolism</subject><subject>Inhibitor drugs</subject><subject>Inhibitory Concentration 50</subject><subject>Laboratory animals</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Myocytes, Cardiac 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activity</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>30</volume><issue>1</issue><spage>130</spage><epage>143</epage><pages>130-143</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>Summary
The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>20862515</pmid><doi>10.1007/s10637-010-9542-z</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 2012-02, Vol.30 (1), p.130-143 |
| issn | 0167-6997 1573-0646 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Angiogenesis Angiogenic Proteins - metabolism Animals Antibodies Antibodies - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - toxicity Apoptosis Astrocytes - drug effects Astrocytes - pathology Brain Neoplasms - enzymology Brain Neoplasms - pathology Breast cancer Breast Neoplasms - enzymology Breast Neoplasms - immunology Breast Neoplasms - pathology Butyrates - pharmacology Cardiomyocytes Cardiotoxicity Cell Line, Tumor Cell Survival - drug effects Cells Cytoprotection Cytotoxicity Dose-Response Relationship, Drug Doxorubicin - pharmacology Drug dosages Drug Synergism Female Fibroblasts - drug effects Fibroblasts - pathology Gene expression Glioblastoma - enzymology Glioblastoma - pathology Growth factors Histone Deacetylase Inhibitors - pharmacology Humans Inflammation Mediators - metabolism Inhibitor drugs Inhibitory Concentration 50 Laboratory animals Medicine Medicine & Public Health Mice Mice, Inbred BALB C Myocytes, Cardiac - drug effects Myocytes, Cardiac - pathology Oncology Organophosphorus Compounds - pharmacology Pharmacology Pharmacology/Toxicology Preclinical Studies Proteins Rats Reactive Oxygen Species - metabolism Receptor, ErbB-2 - immunology Studies Testing laboratories Time Factors Toxicity Tumor necrosis factor-TNF |
| title | The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T16%3A26%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20histone%20deacetylase%20inhibitor%20butyroyloxymethyl%20diethylphosphate%20(AN-7)%20protects%20normal%20cells%20against%20toxicity%20of%20anticancer%20agents%20while%20augmenting%20their%20anticancer%20activity&rft.jtitle=Investigational%20new%20drugs&rft.au=Tarasenko,%20Nataly&rft.date=2012-02-01&rft.volume=30&rft.issue=1&rft.spage=130&rft.epage=143&rft.pages=130-143&rft.issn=0167-6997&rft.eissn=1573-0646&rft.coden=INNDDK&rft_id=info:doi/10.1007/s10637-010-9542-z&rft_dat=%3Cproquest_cross%3E2789222401%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1112132608&rft_id=info:pmid/20862515&rfr_iscdi=true |