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The Histone Deacetylase Inhibitor Valproic Acid Sensitizes Gemcitabine-Induced Cytotoxicity in Gemcitabine-Resistant Pancreatic Cancer Cells Possibly Through Inhibition of the DNA Repair Protein Gamma-H2AX

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Abstract

Background

Gemcitabine (GEM) remains a major chemotherapeutic drug for pancreatic cancer, but resistance to GEM has been a big problem, as its response rate has been decreasing year by year.

Methods

The effect of the histone deacetylase inhibitor (HDAI) valproic acid (VPA) was compared with tranilast and RI-1 as a combinatorial treatment with GEM in four pancreatic cancer cell lines, BxPC-3, PK45p, MiaPaCa-2 and PK59. Cell viability assays were carried out to check the cytotoxic effects, western blotting was carried out for DNA repair mechanisms, and localization was determined by immunofluorescence.

Results

The sensitization factors (i.e., the fold ratio of cell viability for GEM/GEM plus drug) reveal that VPA increases the cytotoxic sensitization to GEM at approximately 2.7-fold, 1.2-fold, 1.5-fold and 2.2-fold in BxPC-3, MiaPaCa-2, PK-45p and PK-59 cell lines, respectively. Moreover, GEM induces activation of the DNA repair protein H2AX proportional to the dosage. Interestingly, however, this effect can be abrogated by VPA.

Conclusions

These results indicate that VPA enhances GEM-induced cytotoxicity in GEM-resistant pancreatic cancer cells, possibly through inhibition of DNA damage signaling and repair. Our study suggests VPA as a potential therapeutic agent for combinatorial treatment with GEM in pancreatic cancer.

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Acknowledgments

This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (NO. 24501352 to Yasuhiro Kuramitsu). Immunoblot detection by LAS-1000 and plasmid construction were done at the Gene Research Center of Yamaguchi University.

Conflict of Interest

Y. Wang, Y. Kuramitsu, T. Kitagawa, K. Tokuda, B. Baron, J.Akada and K. Nakamura have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate school of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Yufeng Wang, Yasuhiro Kuramitsu, Takao Kitagawa, Kazuhiro Tokuda, Byron Baron, Junko Akada & Kazuyuki Nakamura

  2. Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan

    Kazuyuki Nakamura

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  1. Yufeng Wang
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  2. Yasuhiro Kuramitsu
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Correspondence to Yasuhiro Kuramitsu.

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Wang, Y., Kuramitsu, Y., Kitagawa, T. et al. The Histone Deacetylase Inhibitor Valproic Acid Sensitizes Gemcitabine-Induced Cytotoxicity in Gemcitabine-Resistant Pancreatic Cancer Cells Possibly Through Inhibition of the DNA Repair Protein Gamma-H2AX. Targ Oncol 10, 575–581 (2015). https://doi.org/10.1007/s11523-015-0370-0

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  • DOI: https://doi.org/10.1007/s11523-015-0370-0

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