Morimoto Yoshihito, Takada Kimihiko, Takeuchi Osamu, Watanabe Kazuhiro, Hirohara Masayoshi, Masuda Yutaka
Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan.
BioMedical Laboratory, Department of Research, Kitasato Institute Hospital, Tokyo, Japan.
J Chemother. 2023 Sep;35(5):435-447. doi: 10.1080/1120009X.2022.2125749. Epub 2022 Sep 22.
We previously showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, and navitoclax, a Bcl-2 and Bcl-xL inhibitor, induced a synergistic inhibitory effect on cell proliferation . Here, we investigated the effect of the simultaneous knockdown of Chk1 and each antiapoptotic protein of the Bcl-2 family (Bcl-2, Bcl-xL, or Mcl-1) with small interfering RNAs on apoptosis in three pancreatic cancer cell lines. Only simultaneous knockdown of Chk1 and Bcl-xL induced significant apoptosis compared with single knockdown in all three cell lines. We evaluated the anti-tumour effects of combined prexasertib and navitoclax treatment in a mouse xenograft model. Treatment to control volume ratios were calculated as 63.2% for prexasertib, 79.4% for navitoclax, and 36.8% for prexasertib and navitoclax. These findings suggest that the simultaneous inhibition of Chk1 and Bcl-xL may be an effective treatment for pancreatic cancer.
我们之前表明，检查点激酶1（Chk1）抑制剂prexasertib和Bcl-2及Bcl-xL抑制剂navitoclax对细胞增殖具有协同抑制作用。在此，我们用小干扰RNA研究了同时敲低Chk1和Bcl-2家族的各抗凋亡蛋白（Bcl-2、Bcl-xL或Mcl-1）对三种胰腺癌细胞系凋亡的影响。与在所有三种细胞系中的单独敲低相比，只有同时敲低Chk1和Bcl-xL诱导了显著的凋亡。我们在小鼠异种移植模型中评估了联合使用prexasertib和navitoclax治疗的抗肿瘤效果。治疗与对照体积比计算得出，prexasertib为63.2%，navitoclax为79.4%，prexasertib和navitoclax联合为36.8%。这些发现表明，同时抑制Chk1和Bcl-xL可能是胰腺癌的一种有效治疗方法。
