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.
Highlights
Pancreatic adenocarcinoma is the fourth leading cause of cancerrelated deaths in the Western world [1]
It has been reported that inhibition of Checkpoint kinase 2 (CHK2) activity by selective CHK2 inhibitors enhanced the cytotoxic effects of several chemotherapeutic agents [30], Topoisomerase I inhibitors [31] and PARP inhibitors [32]
We examined whether inhibition of CHK2 would enhance the sensitivity of pancreatic cancer cells to GEM
Summary
Pancreatic adenocarcinoma is the fourth leading cause of cancerrelated deaths in the Western world [1]. In the United States, approximately 43,000 new cases and 37,000 deaths of pancreatic cancer were estimated in 2010 [1]. The overall prognosis of pancreatic cancer patients is extremely poor: the 5-year survival rate is estimated less than 5–6% [2]. The front-line standard drug, gemcitabine (GEM), is used for the treatment of advanced human pancreatic cancer either alone or in combination with other chemotherapeutic agents [4,5,6]. While response rates and progression-free survival have slightly improved, the efficacy is still limited and novel therapies are urgently needed
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