The Growth Inhibition Of Valproic Acid In Human Gastric Cancer Drug-resistant Cell Line And The Synergistic Effect Combined With Chemotherapeutic Drugs

Objective:1. To investigate the influence of valproic acid(VPA) on proliferation, the cell cycle and apoptosis in human gastric cancer drug-resistant cell line SGC7901/VCR.2. To investigate the effect of valproic acid combined with chemotherapeutics(5-FU,DDP,ADM) in human gastric cancer drug-resistant cell line SGC7901/VCR, and provide experimental basis for clinical treatment of gastric cancer.Methods:The histone deacetylase inhibitors(HDACIs) valproic acid was given alone or as a doublet with 5-FU, DDP or ADM in human gastric cancer cell SGC7901/VCR. The inhibition of proliferation was analyzed with tetrazolium blue (MTT) assay. The interactions between valproic acid and chemotherapeutic drugs were analyzed by Chou-Talalay's combination index(CI). Different concentrations of valproic acid was given to human gastric cancer cells to observe cell morphology. Flow cytometric analysis was used to detect the cell cycle and apoptosis of the gastric cancer cells.Results:1. VPA alone inhibited the growth of SGC7901/VCR and SGC7901 gastric cancer cells in a time and dose-dependent manner, the difference showed significant(P<0.05), growth inhibition between SGC7901 and SGC7901/VCR was similar. After treated with VPA for 48 hours, SGC7901/VCR cells underwent dramatic changes in morphology.2. Flow cytometry assay indicated that most of the cells were arrested in GO/G1 phase, the percentage of cells in S phase decreased, the difference showed significant(P<0.05), excepct the 0.5mM group compared with the control group, the change was in a dose-dependent manner, G2/M phase had no significant changes (P>0.05). VPA alone induced apoptosis in SGC7901/VCR cells in a dose-dependent manner, the difference showed significant(P<0.01).3. VPA, when administered together with 5-FU, DDP or ADM, showed a strong synergistic effect, the IC50 values were less than the chemotherapeutic drug alone, and the CI values were less than 1, excepct DDP had one group larger than 1. When the inhibition rate reached 22%, the effect of VPA in combination with 5-FU was synergistic, when the inhibition rate reached 18%, the effect of VPA in combination with DDP was synergistic, when the inhibition rate reached 36%, the effect of VPA in combination with ADM was synergistic.Conclusions:1. In a certain range of concentration, VPA could inhibit the proliferation of SGC7901/VCR cells in a time and dose-dependent manner.2. The inhibitory effect of VPA on SGC7901/VCR cells may through arresting the cell cycle and inducing apoptosis.3. VPA in combination with chemotherapeutics 5-FU, DDP or ADM had synergistic antitumor effects.