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

Author:
Qiao, Zhixin, Ren, Suping, Li, Weijing, Wang, Xuanlin, He, Min, Guo, Yingjie, Sun, Liwei, He, Yuezhong, Ge, Yubin, Yu, Qun
Source:
Biochemical and biophysical research communications 2013 v.434 pp. 95-101
ISSN:
0006-291X
Subject:
mitochondrial membrane, DNA damage, histone deacetylase, cell growth, humans, membrane potential, cytotoxicity, pancreatic neoplasms, prognosis, models, antineoplastic agents, neoplasm cells, interphase, apoptosis, anticarcinogenic activity
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.
Agid:
897354