Document Detail


The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity.
MedLine Citation:
PMID:  20862515     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-23
Journal Detail:
Title:  Investigational new drugs     Volume:  30     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-12     Completed Date:  2012-05-08     Revised Date:  2012-10-12    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  130-43     Citation Subset:  IM    
Affiliation:
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach-Tikva 49100, Israel.
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MeSH Terms
Descriptor/Qualifier:
Angiogenic Proteins / 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:
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

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