Abstract:

Objective Valproic acid (VPA) is an established drug in the long-term therapy of seizure disorders. Recently, VPA has been associated with anticancer activity, an effect thought to be produced by inhibition of cellular histone deacetylase 1.  Methods  The PC3 cell line tumor xenografts was established. Animals in the experimental group were given 0.4% VPA in their drinking water until tumors reached 5 mm in the longest dimension. At the end of day 28, tumors were harvested, whole blood was collected and serum was analyzed for VPA, liver function tests (transaminases) and complete blood count. The DNA strand breaks were identified by the terminal deoxynucleotidyltransferasemediated UTP end labeling technique using the in situ Cell Death Detection Kit. Effects of VPA on histone acetylation and p21WAF/CIP gene expression were investigated by Western blot. Ki67 and p21WAF/CIP were detected by Immunohistochemistry in tissues of PC3 cell line tumor xenografts. ResultsChronic VPA treatment resulted in statistically significant reduction of tumor xenograft growth in vivo. Tumor volumes were measured and compared using the Wilcoxon ranksum test and 2way ANOVA with posthoc testing. Animals treated with VPA showed a statistically significant decrease in tumor volume compared with controls with 77.27% growth inhibition. Treatment of xenografts with VPA induced a significant increase in levels of acetylated histone H3 and p21WAF/CIP compared with the controls (P＜0.01). In the VPA treated tumors, apoptotic cell death was markedly increased compared with the control tumors (P＜0.01). Ki67 expression in the control group was stronger than in the experimental group (P＜0.01). Conclusion  We conclude that chronic administration of VPA results in a significant reduction in PC3 cell line tumor xenograft volume in vivo. These data provide compelling evidence that additional studies are warranted in evaluating the potential use of chronic VPA as a means of altering androgen independent prostate cancer cell growth and progression.

Key words: Prostate tumor; Valproic acid; Proliferation; Apoptosis; Mice, nude