BACKGROUND & AIMS:
:In our previous study, we showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, enhances the effects of standard drugs for pancreatic cancer, including gemcitabine (GEM), S-1, and the combination of GEM and S-1 (GS). The combination of prexasertib and GS has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating anti-apoptotic protein Bcl-2. In the present study, we investigated the combined effect of GEM, S-1, and prexasertib with a selective Bcl-2 inhibitor (venetoclax) and a non-selective Bcl-2 inhibitor (navitoclax) in SUIT-2 pancreatic cancer cells. An MTT assay revealed that the combination of prexasertib with navitoclax showed a synergistic effect but the combination with venetoclax did not. Investigation of the pancreatic cancer cell lines SUIT-2, MIA PaCa-2, and BxPC-3 revealed that BxPC-3 also showed a high synergistic effect when combined with prexasertib and navitoclax but not venetoclax. Mechanistic analysis of the combined effect showed that apoptosis was induced. Bcl-2 knockdown with siRNA and prexasertib treatment did not induce apoptosis, whereas Bcl-xL knockdown with siRNA and prexasertib treatment resulted in strong induction of apoptosis. In addition, among the three cell lines, the combined effect of prexasertib and navitoclax resulted in increased apoptotic cell death because the protein expression levels of Bcl-xL and Chk1 were higher. Our results demonstrate that the combination of prexasertib and navitoclax has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating Bcl-xL. Simultaneous inhibition of Chk1 and Bcl-xL could be a new strategy for treating pancreatic cancer.
背景与目标:
: 在我们先前的研究中,我们表明,检查点激酶1 (Chk1) 抑制剂prexasertib增强了胰腺癌标准药物的作用,包括吉西他滨 (GEM),S-1以及GEM和S-1 (GS) 的组合。Prexertib和GS的组合具有很强的抗肿瘤作用,并通过下调抗凋亡蛋白Bcl-2来诱导胰腺癌细胞的凋亡。在本研究中,我们研究了GEM,S-1和prexasertib与选择性Bcl-2抑制剂 (venetoclax) 和非选择性Bcl-2抑制剂 (navitoclax) 在SUIT-2胰腺癌细胞中的联合作用。MTT分析显示,prexasertib与navitoclax的组合显示出协同作用,但与venetoclax的组合却没有。对胰腺癌细胞系SUIT-2,MIA PaCa-2和BxPC-3的研究表明,BxPC-3与prexasertib和navitoclax联合使用时也显示出很高的协同作用,而非venetoclax。综合效应的机理分析表明,诱导了细胞凋亡。siRNA和prexasertib处理的Bcl-2敲除不会诱导细胞凋亡,而siRNA和prexasertib处理的Bcl-xL敲除会导致细胞凋亡的强烈诱导。此外,在这三种细胞系中,prexasertib和navitoclax的联合作用导致凋亡细胞死亡增加,因为Bcl-xL和Chk1的蛋白表达水平较高。我们的结果表明,prexasertib和navitoclax的组合具有很强的抗肿瘤作用,并通过下调Bcl-xL诱导胰腺癌细胞凋亡。同时抑制Chk1和Bcl-xL可能是治疗胰腺癌的新策略。