Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells.

Abstract

Pancreatic cancer is a lethal human malignancy with an extremely poor prognosis and urgently requires new therapies. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents and have shown promising antitumor activities in preclinical models of pancreatic cancer. In this study, we sought to determine the antitumor effects of a novel HDACI, chidamide (CS055), in pancreatic cancer cells alone or in combination with gemcitabine. Treatments of BxPC-3 or PANC-1 pancreatic cancer cell lines with chidamide resulted in dose- and time-dependent growth arrest, accompanied by induction of p21 expression. When combined in a sequential schedule, chidamide synergistically enhanced gemcitabine-induced cell growth arrest and apoptosis, accompanied by cooperative downregulation of Mcl-1 and loss of mitochondrial membrane potential (ΔΨm). Chidamide enhanced gemcitabine-induced DNA double-strand breaks and S phase arrest, and abrogated the G2/M cell cycle checkpoint, potentially through suppression of CHK1 expression. Our results suggest that chidamide has a therapeutic potential for treating pancreatic cancer, especially in combination with gemcitabine.

• Authors: Zhixin Qiao, Suping Ren, Weijing Li, Xuanlin Wang, Min He, Yingjie Guo, Liwei Sun, Yuezhong He, Yubin Ge, Qun Yu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 434 Issue 1 Pg. 95-101 (Apr 26 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23541946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Aminopyridines
• Antimetabolites, Antineoplastic
• Benzamides
• Histone Deacetylase Inhibitors
• Deoxycytidine
• N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
• Gemcitabine

Topics

• Aminopyridines (administration & dosage)
• Antimetabolites, Antineoplastic (administration & dosage)
• Benzamides (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deoxycytidine (administration & dosage, analogs & derivatives, toxicity)
• Drug Synergism
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Pancreatic Neoplasms (drug therapy, enzymology, pathology)
• Up-Regulation (drug effects)
• Gemcitabine