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

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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, p21Waf1, 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 102 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 p21Waf1, 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 p21Waf1 expression.

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Acknowledgments

Grant support was provided by the Research Support Foundation of The University of Tokushima and TAIHO Pharmaceutical Co., Ltd., and the Grants-in-Aid for Scientific Researches of the Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research B: No. 20390359). We would like to thank Ms. Harada for providing technical assistance.

Conflict of interest

M. Shimada has received research funding from Merck Sharp and Dohme Corp. The other authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City, 770-8503, Japan

    Shuichi Iwahashi, Mitsuo Shimada, Tohru Utsunomiya, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Hiroki Mori, Jun Hanaoka, Koji Sugimoto & Yu Saito

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  1. Shuichi Iwahashi
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Correspondence to Mitsuo Shimada.

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Iwahashi, S., Shimada, M., Utsunomiya, T. et al. Histone deacetylase inhibitor augments anti-tumor effect of gemcitabine and pegylated interferon-α on pancreatic cancer cells. Int J Clin Oncol 16, 671–678 (2011). https://doi.org/10.1007/s10147-011-0246-y

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  • DOI: https://doi.org/10.1007/s10147-011-0246-y

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