Document Detail


Effect of valproic acid on radiation-induced DNA damage in euchromatic and heterochromatic compartments.
MedLine Citation:
PMID:  18239454     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The distinction between heterochromatin and euchromatin in the double-strand break (DSB) damage pathway is of interest, recent reports indicate that chromatin is not created equally nor is it acquiescent to DSBs. Using the classical histone deacetylase inhibitor, Trichostatin A, we have previously demonstrated that chromatin represents a heterogeneous substrate with respect to histone tail modification by histone deacetylase inhibitors and consequent responses to DNA damage and repair. Here, we extended the initial findings by investigating the radiation sensitizing properties of the widely used antiepileptic, valproic acid. Clonogenic survival assays confirm that valproic acid is an efficient sensitizer of radiation-induced cell death. The radiosensitizing effect is correlated with valproic acid-mediated histone hyperacetylation, chromatin decondensation and enhanced formation of radiation-induced gammaH2AX preferentially on euchromatic alleles. Heterochromatin was much more resistant to histone tail modification, changes in chromatin architecture and DNA damage. These findings are consolidated by studies with the structurally related analogue, valpromide, which does not inhibit histone deacetylase enzymes. At a relatively low concentration (1 mM) valpromide did not cause chromatin modifications and radiation sensitivity, providing further evidence that the radiation sensitizing properties of valproic acid are at least in part, due to histone modification-dependent effects on euchromatin. When higher concentrations (5 mM) were used, both compounds resulted in significant radiation sensitivity, albeit, with differing efficacy (dose modifying factors of 1.5 and 1.2 for valproic acid and valpromide, respectively). The findings imply that histone-modification independent mechanisms also contribute to the radiation sensitizing properties of valproic acid. Overall, our findings are consistent with the emerging interest in the use histone deacetylase inhibitors in combination with radiotherapy for the treatment of cancer.
Authors:
K N Harikrishnan; Tom C Karagiannis; Maggie Z Chow; Assam El-Osta
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-12-04
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  7     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-04-21     Completed Date:  2008-06-16     Revised Date:  2008-09-23    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  468-76     Citation Subset:  IM    
Affiliation:
Epigenetics in Human Health and Disease, Baker Medical Research Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Cell Death / drug effects,  radiation effects*
Cell Line, Tumor
Chromatin Immunoprecipitation
DNA Breaks, Double-Stranded*
Dose-Response Relationship, Drug
Euchromatin / drug effects*
Gamma Rays
Heterochromatin / drug effects*
Histones / metabolism
Humans
Radiation-Sensitizing Agents / pharmacology*
Radiotherapy / methods*
Survival Analysis
Valproic Acid / chemistry,  pharmacology*
Chemical
Reg. No./Substance:
0/Euchromatin; 0/Heterochromatin; 0/Histones; 0/Radiation-Sensitizing Agents; 99-66-1/Valproic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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