Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma

Kais Zakharia; Katsuyuki Miyabe; Yu Wang; Dehai Wu; Catherine D Moser; Mitesh J Borad; Lewis R Roberts

doi:10.1016/j.tranon.2018.09.005

Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma

Transl Oncol. 2019 Jan;12(1):143-153. doi: 10.1016/j.tranon.2018.09.005. Epub 2018 Oct 11.

Authors

Kais Zakharia¹, Katsuyuki Miyabe², Yu Wang³, Dehai Wu², Catherine D Moser², Mitesh J Borad⁴, Lewis R Roberts⁵

Affiliations

¹ Internal Medicine Residency Program, Department of Medical Education, Beaumont Health - Dearborn, Oakwood Campus, Dearborn, MI, USA; Division of Gastroenterology and Hepatology, University of Iowa, Iowa City, IA, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
² Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
³ Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁴ Division of Hematology, Division of Oncology, Mayo Clinic, Scottsdale, AZ, USA.
⁵ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. Electronic address: roberts.lewis@mayo.edu.

Abstract

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.

Abstract

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