| The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity. | |
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MedLine Citation:
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PMID: 20862515 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Nataly Tarasenko; Gania Kessler-Icekson; Pnina Boer; Aida Inbal; Hadassa Schlesinger; Don R Phillips; Suzanne M Cutts; Abraham Nudelman; Ada Rephaeli |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-23 |
Journal Detail:
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Title: Investigational new drugs Volume: 30 ISSN: 1573-0646 ISO Abbreviation: Invest New Drugs Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-01-12 Completed Date: 2012-05-08 Revised Date: 2012-10-12 |
Medline Journal Info:
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Nlm Unique ID: 8309330 Medline TA: Invest New Drugs Country: United States |
Other Details:
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Languages: eng Pagination: 130-43 Citation Subset: IM |
Affiliation:
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Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach-Tikva 49100, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiogenic Proteins
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metabolism Animals Antibodies / pharmacology Antineoplastic Combined Chemotherapy Protocols / pharmacology*, toxicity Astrocytes / drug effects*, pathology Brain Neoplasms / enzymology, pathology* Breast Neoplasms / enzymology, immunology, pathology* Butyric Acids / pharmacology Cell Line, Tumor Cell Survival / drug effects Cytoprotection Dose-Response Relationship, Drug Doxorubicin / pharmacology Drug Synergism Female Fibroblasts / drug effects*, pathology Glioblastoma / enzymology, pathology* Histone Deacetylase Inhibitors / pharmacology Humans Inflammation Mediators / metabolism Inhibitory Concentration 50 Mice Mice, Inbred BALB C Myocytes, Cardiac / drug effects*, pathology Organophosphorus Compounds / pharmacology Rats Reactive Oxygen Species / metabolism Receptor, erbB-2 / immunology Time Factors |
| Chemical | |
Reg. No./Substance:
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0/AN-7 phosphate cpd; 0/Angiogenic Proteins; 0/Antibodies; 0/Butyric Acids; 0/Histone Deacetylase Inhibitors; 0/Inflammation Mediators; 0/Organophosphorus Compounds; 0/Reactive Oxygen Species; 23214-92-8/Doxorubicin; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, erbB-2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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