Anticancer Effects Of Valproic Acid On Human Ovarian Cancer In Nude Mice

Objective: To investigate the effects of valproic acid (VPA) used alone and in combination with diamminedichloroplatinum (DDP) on the growth of human ovarian cancer transplanted subcutaneously in nude mice.Methods: Human ovarian cancer model transplanted subcutaneously in nude mice was established, and divided into 4 groups: (1)control group; (2)experimental group, including: VPA group, DDP group and VPA+DDP group. Tumor volume and weight were detected. Flowcytometry(FCM) was used to assess the characters of apoptosis in the tissues of tumor, liver and brain. The VEGF, E-cadherin and MMP-9 protein level were determined by Flowcytometry.Results: (1)In subcutaneous tumor model the dimension of the tumor in experimental group is smaller than that in the control group. The longer VPA being used the smaller the tumors were. The inhibiting rate of VPA group, DDP group and VPA+DDP group were as follows: 40.7%, 45.3%, 58.0%, they were significantly higher than control group(P<0.01).(2)Under light, a number of characteristic apoptotic cells were found in tumors of experimental groups. However, in the control groups there was few. The apoptotic rate of experimental groups were as follows: (27.05±1.63) %, (35.93±3.89) %, (42.59±2.55)%, which were significantly higher than control group (16.73±2.82)% (P<0.01). The cell cycle distribution changed in experimental groups, the G1-phase was increase but the S-phase was decrease.(3) There was no toxic reaction during the course. The apoptotic rates of the liver and brain tissues in nude mice were very low(P>0.05).(4)The result of FCM indicated that after using VPA, the expression of E-cadherin was increased but the expression of VEGF and MMP-9 were decreased, and there was a significant difference among each group(P<0.05).Conclusions: (1) VPA can significantly inhibit the growth of the epithelial ovarian cancer SKOV3 cells in vivo without toxic side effects.(2) The key mechanism of cell growth inhibition by VPA in tumor growth may relate to the induction of cell cycle arrest and apoptosis.(3) Treated with VPA combined with DDP can enhance anticancer effects without toxic side effects.(4) VPA can decrease the expression of MMP-9 protein and increase the expression of E-cadherin protein. VPA may inhibit the metastasis of ovarian cancer.(5)VPA can decrease the expression of VEGF protein. VPA may inhibit the growth of ovarian cancer by inhibiting the neoplasms angiogenesis.(6)This study suggests that VPA could be a perspective and novel attractive agent for treatment of ovarian cancer.