Abstract 1004: Histone deacetylase inhibitors: Potential epigenetic therapeutic drugs for cholangiocarcinoma.
Authors: Limpaiboon Temduang , Sriraksa Ruethairat 
Published: August 2014

Cholangiocarcinoma (CCA), a cancer of biliary epithelium, is a rare tumor with poor prognosis which has been increasing markedly worldwide in the past decade. The surgical resection remains a potentially curative treatment of CCA. Due to the late clinical presentation, a small number of patients can undergo for surgery. Adjuvant therapy such as chemotherapy and radiotherapy has been used for CCA. Although various chemotherapeutic agents e.g. 5-fluorouracil (5-FU), gemcitabine, and cisplatin, either alone or in combination, have been widely used in CCA, the response rate is very poor with a partial response approximately 10-20%. Therefore, new agents and innovative approaches of therapy are important subjects focusing in effective treatment of CCA. Histone deacetylases (HDACs) mediate deacetylation of acetylated histones resulting in chromatin condensation and transcriptional repression. HDAC inhibitors (HDACIs) inhibit the deacetylation of histones and weaken the histone-DNA interactions, thereby permitting a more relaxed conformation of chromatin which contributes to increasing gene transcription and enabling to induce differentiation, cell cycle arrest, and apoptosis of tumor cells. Recently, HDACIs are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies with relatively resistant in normal cells. According to chemical structures, HDACIs can be classified into several groups such as sodium butyrate, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA). The authors aimed to investigate the mRNA expression of HDACs1-10 in a panel of CCA derived cell lines (M213, M214 and KKU-100) and an immortal biliary cell line (MMNK1) using semi-quantitative reverse transcription-polymerase chain reaction. The inhibitory effect of VPA and SAHA, either as a single agent or combination with classical chemotherapeutic drug, 5-FU on cell proliferation was determined by sulforhodamine B assay.

The result showed that HDACs 1-10 were expressed in all cell types studied suggesting that histone deacetylation is one of epigenetic mechanisms mediating aberrantly silenced genes in CCA. Both VPA and SAHA inhibited cell proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less sensitive to 5-FU showed highly sensitive to both VPA and SAHA. Simultaneously combined sub-toxic doses of HDACIs and 5-FU significantly inhibited cell proliferation in CCA cell lines compared to single agent treatment (P ≤ 0.01), while sequentially combined treatments exhibited lower responsiveness. This study suggests the prospective administration of HDACIs as potential epigenetic therapeutic drugs for CCA treatment efficacy.

Citation Format: Temduang Limpaiboon, Ruethairat Sriraksa. Histone deacetylase inhibitors: Potential epigenetic therapeutic drugs for cholangiocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1004. doi:10.1158/1538-7445.AM2013-1004