期刊
TRANSLATIONAL ONCOLOGY
卷 12, 期 1, 页码 143-153出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.tranon.2018.09.005
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资金
- National Institutes of Health [CA165076]
- Mayo Clinic Center for Cell Signaling in Gastroenterology [NIDDK P30DK084567]
- Cholangiocarcinoma Foundation
- Mayo Clinic Cancer Center [CA15083]
- Mayo Foundation
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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