Effect of histone deacetylase inhibitor in combination with gemcitabine on pancreas cancer and cholangiocarcinoma cell line.

Abstract

e14645 Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors (HDACIs) induce the differentiation or apoptosis of cancer cells. Valproic acid (VPA) is one of the clinically available HDACIs. On the other hand, the anticancer effects of IFNα have also been reported. Methods: Human pancreas cancer cell lines (SUIT-2, BxPC3) and a cholangiocarcinoma cell line (HuCCT1) were used. The anticancer effects of VPA combined with gemcitabine (GEM) and IFNα were examined in SUIT-2 and BxPC3, and the effects of VPA combined with GEM were studied in HuCCT1. The cell viability was evaluated by MTT assay, and the gene-expressions of P21, HDAC, VEGF, and HIF-1 were evaluated by RT-PCR. Results: Pancreas cancer cell lines: VPA (0.5mM) did not suppress the cell viability. IFNα (102E) weakly suppressed it by 28% in BxPC3 and 17% in SUIT-2. GEM (5 nM) reduced by 36% in BxPC3 and 61% in SUIT-2. The combination of GEM and IFNα showed the strong suppression by 82% in SUIT-2 and 51% in BxPC3, which was further augmented by the addition of VPA up to 88% and 67%, respectively (p < 0.05). The combination of GEM and IFNα showed the enhanced expression of p21, which was also reinforced by VPA (p < 0.01). GEM combined with VPA reduced the HDAC expressions, while such combination effects were not observed in VEGF or HIF-1 expressions.Cholangiocarcinoma cell line: GEM (5 nM) did not suppress the cell viability, GEM (10 nM) suppressed by 16%. VPA (0.5 mM) did not suppress the cell viability, while VPA (1.0 mM) weakly decreased it by 12% and VPA (5.0 mM) suppressed by 35%. GEM (5nM) and VPA (0.5 mM) reduced by 23%, which significantly augmented the anticancer effect of GEM alone or VPA alone (p < 0.01). Furthermore, GEM combined with VPA up-regulated the p21 expression compare to single agent (p < 0.05). Conclusions: VPA augmented the effects of anticancer agents in both the pancreas cancer cell lines and a cholangiocarcinoma cell line. Such effects may be owing to the up-regulated gene-expression of the cyclin dependent kinase inhibitor p21. No significant financial relationships to disclose.