Valproic acid exhibits biphasic effects on apoptotic cell death of activated lymphocytes through differential modulation of multiple signaling pathways

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, possesses potent anti-tumor activity against a variety of malignant cells. However, its action on lymphocytes and the underlying mechanism are not completely understood. In this study, we aimed to analyze the effects of VPA on the proliferation, activation, and apoptosis of murine lymphocytes activated with concanavalin A (ConA). Our results showed that VPA inhibited the proliferation of ConA-activated lymphocytes in a dose-dependent manner. Low-dose VPA (<= 1.1 mM) enhanced CD69 expression on the activated lymphocytes, whereas at high doses (>= 3.3 mM) it decreased CD69 expression. Furthermore, VPA reduced activation-induced apoptotic cell death at low doses, but at high doses it promoted apoptotic cell death of activated lymphocytes dramatically. It was found that the Bax/Bcl-2 ratio and phosphorylation of histone H2A.X was decreased at low doses of VPA but was increased at high doses. The phosphorylation of STAT3 was also differentially regulated by different doses of VPA. VPA, at 5 mM induced the phosphorylation of p38 but not JNK and extracellular signal-regulated kinase (ERK)1/2. In addition, VPA induced a dose-dependent increase in the acetylation of histone H3. These results demonstrate that VPA exhibits dose-dependent biphasic effect on apoptosis of activated lymphocytes probably through differential modulation of several apoptosis-related signaling pathways.