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

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