Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivo

Aim: Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. We investigated the mechanisms of chronic valproic acid (VPA) inhibiting PC3 cell growth in the study. Methods: We established tumor xenografts of the PC3 cell line and investigated the effect of VPA chronic administration on tumor growth. Apoptosis in tumor tissue was measured using the TUNEL Detection Kit. We detected the effect of VPA chronic administration on histone acetylation; p21CIP1/WAF1 gene expression; vascular endothelial growth factor (VEGF) expression by reverse-transcription Polymerase Chain Reaction (PCR) analysis; immunohistochemistry; and Western Blotting. Result: In mouse models with established subcutaneous prostate (PC3), VPA treatment induced 70% inhibition of tumor growth without overt toxicity. Our result showed that chronic administration of VPA has an effect on tumor growth arrest and the effect was associated with increased histone acetylation, p21CIP1/WAF1 up-regulation, and VEGF down-regulation. Conclusion: We conclude that chronic VPA results in profound decreases in the proliferation of PC3 cells, not only by increasing histone H3 acetylation and up-regulating p21CIP1/WAF1 expression, but also by down-regulating VEGF.