Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma.
Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma.
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DOI：
10.1016/j.tranon.2018.09.005
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发表时间：
2019-01
影响因子：
5
通讯作者：
Roberts LR
中科院分区：
文献类型：
--
作者：
Zakharia K;Miyabe K;Wang Y;Wu D;Moser CD;Borad MJ;Roberts LR
目的：研究酪蛋白激酶II （CK2）抑制剂CX-4945对胆管癌（CCA）的抗肿瘤作用。方法：我们评估了CX-4945单独和/或与吉西他滨和顺铂联合使用对CCA细胞系细胞活力、菌落形成和凋亡的影响，以及对HuCCT1异种移植体内生长的影响。结果：CX-4945剂量依赖性地降低了HuCCT1、EGI-1和Liv27的活力，降低了磷酸化AKT/总AKT和磷酸化PTEN/总PTEN的比率。CX-4945显著提高caspase 3/7活性，且呈剂量和时间依赖性。CX-4945显著增强吉西他滨或顺铂对HuCCT1、EGI-1和Liv27细胞的作用，抑制DNA修复酶XRCC1和MDC1的磷酸化。此外，CX-4945单独可显著抑制HuCCT1小鼠异种移植肿瘤的生长。CX-4945联合吉西他滨和顺铂比CX-4945单用或吉西他滨/顺铂更有效。证实了CX-4945对小鼠异种移植物细胞增殖、凋亡、PI3K/AKT通路和DNA修复的影响。结论：CX-4945对CCA具有抗增殖作用，通过抑制PI3K/AKT通路和DNA修复，增强吉西他滨和顺铂的作用。
PURPOSE: We investigated the antitumor effect of the casein kinase II (CK2) inhibitor CX-4945 on cholangiocarcinoma (CCA). METHODS: We assessed the effect of CX-4945 alone and/or in combination with gemcitabine and cisplatin on cell viability, colony formation, and apoptosis of CCA cell lines and on in vivo growth of HuCCT1 xenografts. RESULTS: CX-4945 dose-dependently decreased viability of HuCCT1, EGI-1, and Liv27 and decreased phospho-AKT/total AKT and phospho-PTEN/total PTEN ratios. CX-4945 significantly increased caspase 3/7 activity in a dose- and time-dependent manner. CX-4945 significantly enhanced the effect of gemcitabine or cisplatin on HuCCT1, EGI-1, and Liv27 cells and inhibited the phosphorylation of DNA repairing enzymes XRCC1 and MDC1. Further, CX-4945 alone significantly inhibited growth of HuCCT1 mouse xenograft tumors. Combining CX-4945 with gemcitabine and cisplatin was more potent than CX-4945 alone or gemcitabine/cisplatin. The effect of CX-4945 on cell proliferation, apoptosis, the PI3K/AKT pathway, and DNA repair was confirmed in the mouse xenografts. CONCLUSION: CX-4945 has an antiproliferative effect on CCA and enhances the effect of gemcitabine and cisplatin through its inhibitory effect on the PI3K/AKT pathway and DNA repair.
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