Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523318303644 |
| _version_ | 1818030381940604928 |
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| author | Kais Zakharia Katsuyuki Miyabe Yu Wang Dehai Wu Catherine D. Moser Mitesh J. Borad Lewis R. Roberts |
| author_facet | Kais Zakharia Katsuyuki Miyabe Yu Wang Dehai Wu Catherine D. Moser Mitesh J. Borad Lewis R. Roberts |
| author_sort | Kais Zakharia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:34:41Z |
| format | Article |
| id | doaj.art-37dfdb0ed2bb44e7ac3708e2c7dc6290 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-10T05:34:41Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-37dfdb0ed2bb44e7ac3708e2c7dc62902022-12-22T02:00:26ZengElsevierTranslational Oncology1936-52332019-01-01121143153Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in CholangiocarcinomaKais Zakharia0Katsuyuki Miyabe1Yu Wang2Dehai Wu3Catherine D. Moser4Mitesh J. Borad5Lewis R. Roberts6Internal 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, USADivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USADepartment of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USADivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USADivision of Hematology, Division of Oncology, Mayo Clinic, Scottsdale, AZ, USADivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Address all correspondence to: Lewis R. Roberts, MB ChB, PhD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN 55905.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.http://www.sciencedirect.com/science/article/pii/S1936523318303644 |
| spellingShingle | Kais Zakharia Katsuyuki Miyabe Yu Wang Dehai Wu Catherine D. Moser Mitesh J. Borad Lewis R. Roberts Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma Translational Oncology |
| title | Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma |
| title_full | Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma |
| title_fullStr | Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma |
| title_full_unstemmed | Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma |
| title_short | Preclinical In Vitro and In Vivo Evidence of an Antitumor Effect of CX-4945, a Casein Kinase II Inhibitor, in Cholangiocarcinoma |
| title_sort | preclinical in vitro and in vivo evidence of an antitumor effect of cx 4945 a casein kinase ii inhibitor in cholangiocarcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S1936523318303644 |
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