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  • Title: 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.
    Author: Wang Y, Kuramitsu Y, Kitagawa T, Tokuda K, Baron B, Akada J, Nakamura K.
    Journal: Target Oncol; 2015 Dec; 10(4):575-81. PubMed ID: 25940934.
    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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