Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer

• DOI: 10.1371/journal.pone.0052095
• Publication Date: 2012-12-14T22:21:35Z
• Authors: Guan Wang; Jing He; Jianyun Zhao; Wenting Yun; Chengzhi Xie; Jeffrey W. Taub; Asfar Azmi; Ramzi M. Mohammad; Yan Dong; Wei Kong; Yingjie Guo; Yubin Ge
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; G2 Phase; 0301 basic medicine; Science; Antineoplastic Agents; Apoptosis; Histone Deacetylases; Histones; 03 medical and health sciences; Tubulin; Cell Line, Tumor; Humans; DNA Breaks, Double-Stranded; Molecular Targeted Therapy; Cell Death; Q; R; Epithelial Cells; Cell Cycle Checkpoints; 3. Good health; Histone Deacetylase Inhibitors; Pancreatic Neoplasms; Medicine; Cell Division; Research Article

Background Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) guide the selection HDAC tailored treatment cancer. Methodology expression seven cell lines and normal human ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- II-selective HDACIs were MTT assays standard isobologram/CompuSyn software analyses. The effects on death, apoptosis cycle progression, H4, alpha-tubulin, p21, γH2AX levels colony formation assays, flow cytometry analysis, blotting, respectively. Results majority classes I II HDACs detected lines, albeit at variable levels. Treatments MGCD0103 (a I-selective HDACI) resulted dose-dependent growth arrest, death/apoptosis, arrest G2/M phase, accompanied induction p21 DNA double-strand breaks (DSBs). contrast, MC1568 IIa-selective Tubastatin A HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, significantly enhanced MGCD0103-induced while only synergistically arrest. Although had no obvious DSBs expression, their cooperative cells. Conclusion Our results suggest that are potential therapeutic targets for treating Accordingly, pan-HDACIs may be more beneficial than class- isoform-selective inhibitors.