Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine

Hong Quan Duong, Young Bin Hong, Jung Soon Kim, Hee Seok Lee, Yong Weon Yi, Yeon Jeong Kim, Antai Wang, Wenjing Zhao, Chi Heum Cho, Yeon Sun Seong, Insoo Bae

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1261-1270
Number of pages10
JournalJournal of Cellular and Molecular Medicine
Volume17
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cell Biology

Keywords

  • Checkpoint kinase 2 (CHK2) inhibitor
  • Combination
  • Gemcitabine
  • NSC109555
  • Pancreatic adenocarcinoma
  • Synergism

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