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

Abstract:

: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 gamma-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.

journal_name

Mol Cancer Ther

authors

Entin-Meer M,Rephaeli A,Yang X,Nudelman A,VandenBerg SR,Haas-Kogan DA

doi

10.1158/1535-7163.MCT-05-0087

keywords:

subject

Has Abstract

pub_date

2005-12-01 00:00:00

pages

1952-61

issue

12

eissn

1535-7163

issn

1538-8514

pii

4/12/1952

journal_volume

4

pub_type

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