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 mediated through the inhibition of cellular
histone deacetylase 1. We investigated the effect of various doses of VPA (0, 1.2, and 5.0 mmol/L) administered either acutely or chronically on
histone acetylation, p21 gene expression,
androgen receptor expression,
prostate-specific antigen (PSA) expression, and cell survival and proliferation in
prostate cancer cell lines. We also studied the effect of chronic VPA on
tumor xenograft growth in vivo. Our results show that acute treatment (3 days) VPA can increase net
histone H3 acetylation and up-regulate p21, AR, and cytosolic PSA expression. Interestingly, the effects on AR and PSA are reversed with chronic treatment. In addition, acute VPA reduces cell survival but has no effect on the subsequent proliferation of surviving cells following drug withdrawal. However, when VPA is chronically administered (10-14 days) to
prostate cancer cells, even lower doses of VPA result in marked decreases in the net proliferation rate, correlating with increased
caspase-2 and
caspase-3 activation. These effects are evident in both
androgen receptor-positive (LNCaP and C4-2) and
androgen receptor-negative (DU145 and PC3)
prostate cancer cells. Moreover, chronic VPA treatment results in statistically significant reduction of
tumor xenograft growth in vivo. We conclude that acute treatment has nominal effects on
prostate cancer cell survival and proliferation, but chronic VPA results in profound decreases in proliferation, independently of
androgen regulation.