title: 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.affiliation: Beijing Institute of Transfusion Medicine, Beijing, PR China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Qiao
authors.forename: Suping
authors.initials: S
authors.lastname: Ren
authors.forename: Weijing
authors.initials: W
authors.lastname: Li
authors.forename: Xuanlin
authors.initials: X
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guo
authors.forename: Liwei
authors.initials: L
authors.lastname: Sun
authors.forename: Yuezhong
authors.initials: Y
authors.lastname: He
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.forename: Qun
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*; D000093542:Gemcitabine
chemical_list: D000631:Aminopyridines; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D003841:Deoxycytidine; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; D000093542:Gemcitabine