title: Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine.
abstract: Checkpoint kinase 2 (CHK2) plays pivotal function as an effector of cell cycle checkpoint arrest following DNA damage. Recently, we found that co-treatment of NSC109555 (a potent and selective CHK2 inhibitor) potentiated the cytotoxic effect of gemcitabine (GEM) in pancreatic cancer MIA PaCa-2 cells. Here, we further examined whether NSC109555 could enhance the antitumour effect of GEM in pancreatic adenocarcinoma cell lines. In this study, the combination treatment of NSC109555 plus GEM demonstrated strong synergistic antitumour effect in four pancreatic cancer cells (MIA PaCa-2, CFPAC-1, Panc-1 and BxPC-3). In addition, the GEM/NSC109555 combination significantly increased the level of intracellular reactive oxygen species (ROS), accompanied by induction of apoptotic cell death. Inhibition of ROS generation by N-acetyl cysteine (NAC) significantly reversed the effect of GEM/NSC109555 in apoptosis and cytotoxicity. Furthermore, genetic knockdown of CHK2 by siRNA enhanced GEM-induced apoptotic cell death. These findings suggest that inhibition of CHK2 would be a beneficial therapeutic approach for pancreatic cancer therapy in clinical treatment.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA; WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Duong
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.forename: Jung Soon
authors.initials: JS
authors.lastname: Kim
authors.forename: Hee-Seok
authors.initials: HS
authors.lastname: Lee
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.forename: Yeon Jeong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Antai
authors.initials: A
authors.lastname: Wang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhao
authors.forename: Chi Heum
authors.initials: CH
authors.lastname: Cho
authors.forename: Yeon-Sun
authors.initials: YS
authors.lastname: Seong
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D017382:Reactive Oxygen Species; D003841:Deoxycytidine; D064447:Checkpoint Kinase 2; D000093542:Gemcitabine
keywords: Checkpoint kinase 2 (CHK2) inhibitor; NSC109555; combination; gemcitabine; pancreatic adenocarcinoma; synergism