Vaproate induces differentiation and apoptosis of myeloid leukemia cells and the related mechanisms

Objective To study the efficacy of sodium valproate (VPA),a histone deacetylase inhibitor (HDACi),in inducing differentiation and apoptosis of myeloid leukemia cells and its possible mechanisms. Method Cell viability and proliferation assays were performed using trypan blue staining and MTT methods. Differentiation and apoptosis markers were analyzed by flow cytometry.The protein level of acetylated histone H3 at lysine 9(H3-Ac-lys9)was detected by Western blot.Results VPA inhibited the proliferation and viability of U937 and K562 cells in a time-and dose-dependent manner.Low concentration(0.5-1 mmol/L)of VPA induced myeloid differentiation in U937 cells,which was demonstrated by up-regulation of CD11b and morphology.When combined with ATRA and/or granulocyte colony-stimulating factor(G-CSF),the induction effect of VPA was remarkably enhanced.High concentration(2 mmol/L) of VPA induced apoptosis of U937 cells as detected by flow cytometry.No differentiation or apoptosis was observed in K562 cells under same condition.U937 and K562 cells presented a significant difference in baseline level of acetylated H3-Ac-lys9.VPA significantly up-regulated the acetylation of H3-Ac-lys9 in U937 cells,but not in k562 cells.Conclusion VPA can induce differentiation and apoptosis in U937 cells,which might be associated with the baseline level of acetylated H3-Ac-lys9 in U937 cells and the sensitivity of H3-Ae-lys9 acetylation after VPA treatment.(Shanghai Med J,2007,30:847-851)