Abstract
BackgroundManagement of peritoneal dissemination is the most critical problem in gastric cancer. This study was performed to investigate the inhibitory effects of valproic acid (VPA) on a highly peritoneal-seeding cell line of human scirrhous gastric cancer, OCUM-2MD3, and to explore the mechanism and the potential of VPA.MethodsThe effects of VPA on the growth of OCUM-2MD3 cells were assessed by MTT assay. In addition, paclitaxel (PTX) was combined with VPA to evaluate their synergistic effects. HDAC1 and HDAC2 expression were evaluated by western blotting in OCUM-2MD3 cells and other gastric cancer cell lines (TMK-1, MKN-28). The acetylation status of histone H3 and α-tubulin after exposure to VPA were analyzed by western blotting. The activities of cell cycle regulatory proteins and apoptosis-modulating proteins were also examined by western blotting. The effects of VPA in vivo were evaluated in a xenograft model, and apoptotic activity was assessed by TUNEL assay.ResultsOCUM-2MD3 cells showed high levels of HDAC1 and HDAC2 expression compared with TMK-1 and MKN-28. The concentration of VPA required for significant inhibition of cell viability (P < 0.05) was 5 mM at 24 h and 0.5 mM at 48 h and 72 h. The inhibition of VPA with PTX showed dose-dependent and combinatorial effects. VPA increased acetyl-histone H3, acetyl-α-tubulin, and p21WAF1 levels accompanied by upregulation of p27, caspase 3, and caspase 9, and downregulation of bcl-2, cyclin D1, and survivin. In the xenograft model experiment, the mean tumor volume of the VPA-treated group was significantly reduced by 36.4%, compared with that of the control group at 4 weeks after treatment (P < 0.01). The apoptotic index was significantly higher in the VPA-treated group (42.3% ± 3.5%) than in the control group (7.7% ± 2.5%) (P < 0.001).ConclusionsVPA induced dynamic modulation of histone H3 and α-tubulin acetylation in relation with the anticancer effect and the enhancement of PTX in the OCUM-2MD3 cell line. Therefore, VPA in combination with PTX is expected to be a promising therapy for peritoneal dissemination of scirrhous gastric cancer.
Highlights
Management of peritoneal dissemination is the most critical problem in gastric cancer
Expression of HDAC1 and HDAC2 in OCUM-2MD3 cells On western blotting analysis, OCUM-2MD3 cells showed high levels of HDAC1 and HDAC2 compared with the other human gastric cancer cell lines (Figure 1)
The HDAC2 expression was characteristically observed in the cells in mitotic phase (Figure 2)
Summary
Management of peritoneal dissemination is the most critical problem in gastric cancer. The recent development of anticancer drugs and intraperitoneal chemotherapy improved the clinical outcomes in gastric cancer patients with peritoneal dissemination [4,5]. Clinical studies indicated that combining molecular targeted agent with conventional chemotherapy enhances the inhibition of tumor growth and metastasis in gastric cancer patients [6,7]. There is increasing evidence that epigenetic alterations, such as histone acetylation and promoter methylation, play important roles in regulation of gene expression associated with the cell cycle and apoptosis [9]. HDAC inhibitors have been shown to have antiproliferative activity through cell cycle arrest, differentiation, and apoptosis in various cancer cell types [15], including gastric cancer cell lines [16,17]. The combination of HDAC inhibitor with conventional chemotherapy is expected to have a synergistic effect, because the mechanism of action is different from those of conventional chemotherapeutic regimens
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