Histone deacetylase inhibitor augments anti-tumor effect of gemcitabine and pegylated interferon-α on pancreatic cancer cells

Abstract

Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitor can induce the differentiation or apoptosis of cancer cells.

Methods: We investigated the anticancer effects of the HDAC inhibitor valproic acid (VPA) in combination with gemcitabine (GEM), an antimetabolic, and pegylated interferon-α2b (PEG-IFN-α2b) in a human pancreatic cancer cell line using a cell proliferation assay. The gene expressions of HDAC1, MTA1, p21(Waf1), and HIF-1 were evaluated by reverse transcription-PCR.

Results: Valproic acid at 0.5 mM when used alone did not suppress cell proliferation. PEG-IFN-α2b at 10(2 )E/ml weakly suppressed cell proliferation in both the BxPC3 (by 28%) and SUIT-2 (by 17%) human pancreatic cancer cell lines. GEM at 5 nM when used alone suppressed cell proliferation by 36 and 61% in the BxPC3 and SUIT-2 cell lines, respectively. The combination treatment of GEM + PEG-IFN-α2b strongly suppressed cell proliferation in the SUIT-2 (82%) and BxPC3 (51%) cell lines, which was further reinforced by the addition of VPA up to 88 and 67%, respectively. The combination treatment of GEM + PEG-IFN-α2b enhanced the expression of p21(Waf1), which was also reinforced by VPA.

Conclusion: VPA augmented the inhibitory effects of PEG-IFN-α2b alone or in combination with PEG-IFN-α2b and GEM on cell proliferation. Such inhibitory effects may be due to the up-regulation of p21(Waf1) expression.