Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas

Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroy...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2005-12, Vol.4 (12), p.1952-1961
Main Authors: Entin-Meer, Michal, Rephaeli, Ada, Yang, Xiaodong, Nudelman, Abraham, VandenBerg, Scott R, Haas-Kogan, Daphne Adele
Format: Article
Language:English
Subjects:
AN-1
AN-9
Antineoplastic Agents - pharmacology
Astrocytes - drug effects
Blotting, Western
Butyric Acid - pharmacology
Caspases - metabolism
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Enzyme Inhibitors - pharmacology
glioma
Glioma - enzymology
Glioma - pathology
HDAC inhibitor
Histone Deacetylase Inhibitors
Histone Deacetylases - metabolism
Humans
Prodrugs - pharmacology
radiation potentiation
Radiation-Sensitizing Agents - pharmacology
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Summary:Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate (AN-1), induced hyperacetylation, increased p21 Cip1 expression, inhibited proliferation, and enhanced apoptosis. Histone deacetylase inhibitor–induced apoptosis was mediated primarily by caspase-8. Treatment of cells with AN-1 or AN-9 for 24 hours before exposure to γ-irradiation potentiated further caspase-8 activity and resultant apoptosis. Clonogenic survival curves revealed marked reductions in cell renewal capacity of U251 MG cells exposed to combinations of AN-1 and radiation. Preliminary in vivo experiments using human glioma cell lines grown as xenografts in mouse flanks suggest in vivo efficacy of AN-9. The data suggest that novel butyric acid prodrugs provide a promising treatment strategy for malignant gliomas as single agents and in combination with radiation therapy. [Mol Cancer Ther 2005;4(12):1952-61]
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-05-0087