The Epigenetic Modifier, Valproic Acid, Enhances Radiation Sensitivity

Abstract

Valproic acid is an established therapeutic for a variety of seizure disorders and incertain cases for depression and anxiety. In addition, valproic acid has been shown topossess histone deacetylase inhibition activity and is currently being investigated asan anti-cancer agent, either alone or in combination with other conventional cancertherapies such as ionizing radiation. In this study, we investigated whether valproicacid modulates cellular responses to radiation in human erythroleukemic, K562 cells.Hyperacetylation of nuclear histones 3 and 4 was used to correlate the effects ofvalproic acid to inhibition of histone deacetylase activity, clonogenic survival,apoptosis and apoptosis. The findings from the clonogenic survival and caspaseinduction assays indicated that pre-treatment of cells with valproic acid for 24 hours,markedly enhanced radiation induced cell-death and apoptosis in K562 cells,respectively. Mechanisms involving drug-mediated cytotoxicity and changes in cellcycle distribution were associated with the radiation sensitizing properties of valproicacid, particularly at the higher concentrations. Overall, our findings are consistentwith the general consensus that HDAC inhibitors efficiently sensitize cancer cells tothe effects of ionizing radiation and support the idea of developing clinically relevantcombinations of HDAC inhibitors and radiotherapy.