title: Inhibitory effect of valproic acid on bladder cancer in combination with chemotherapeutic agentsin vitroandin vivo.
abstract: Histone deacetylase inhibitors (HDACIs) are a promising class of drugs that act as antiproliferative agents by promoting differentiation and inducing apoptosis. Valproic acid (VPA) is an HDACI that has been widely used as an anti-convulsant and shows promise as a chemotherapeutic drug for a number of tumor cells. The present study aimed to investigate the inhibitory effect of VPA on the viability of bladder cancer cells and its synergistic effect with chemotherapeutic agentsin vitroandin vivo. The cell viability of human bladder cancer cell lines following treatment with VPA and/or VPA in combination with mitomycin C, cisplatin (DDP) and adriamycin were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst staining was used to observe the morphology of the apoptotic cells. Survivin protein and acetylated histone H3 levels were quantified using western blot analysis. Thein vivotumor growth inhibition of VPA was determined in rats with N-methyl-N-nitrosourea-induced bladder cancer. VPA significantly inhibited the growth of the bladder cancer cells in a concentration- and time-dependent manner. Furthermore, improved results were achieved for tumor inhibition when VPA was combined with chemotherapeutic agentsin vitroandin vivo. Survivin expression decreased and acetylated histone H3 expression increased in the bladder cancer cells following the treatment with VPA. Intravesical injections of VPA were able to inhibit tumor progression when combined with DDP. In conclusion, VPA acts as an HDACI that has a direct anticancer effect and markedly enhances the action of several chemotherapy agents. VPA may sensitize bladder cancer to anticancer drugs by downregulating survivin expression.
authors.affiliation: Department of Anatomy, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, P.R. China.
authors.forename: Degui
authors.initials: D
authors.lastname: Wang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Jing
authors.forename: Siwei
authors.initials: S
authors.lastname: Ouyang
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhu
authors.forename: Haitao
authors.initials: H
authors.lastname: Niu
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Tian
keywords: apoptosis; bladder cancer; combination; therapy; valproic acid