TY - JOUR
T1 - Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma
AU - Zakharia, Kais
AU - Miyabe, Katsuyuki
AU - Wang, Yu
AU - Wu, Dehai
AU - Moser, Catherine D.
AU - Borad, Mitesh J.
AU - Roberts, Lewis R.
N1 - Funding Information:
Financial support: This work was supported by National Institutes of Health grant CA165076 (to L. R. R.); the Mayo Clinic Center for Cell Signaling in Gastroenterology ( NIDDK P30DK084567 ); The Cholangiocarcinoma Foundation ; the Mayo Clinic Cancer Center ( CA15083 ); and the Mayo Foundation . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Funding Information:
This work was supported by National Institutes of Health grant CA165076 (to L. R. R.); the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567); The Cholangiocarcinoma Foundation; the Mayo Clinic Cancer Center (CA15083); and the Mayo Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. We would also like to show our gratitude to the Senhwa Biosciences for sharing their CX-4945 with us during the course of this research.
Publisher Copyright:
© 2018 The Authors
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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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U2 - 10.1016/j.tranon.2018.09.005
DO - 10.1016/j.tranon.2018.09.005
M3 - Article
AN - SCOPUS:85054449052
SN - 1936-5233
VL - 12
SP - 143
EP - 153
JO - Translational Oncology
JF - Translational Oncology
IS - 1
ER -