A cyclin-dependent kinase inhibitor, dinaciclib in preclinical treatment models of thyroid cancer
We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer. Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measure...
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Published in | PloS one Vol. 12; no. 2; p. e0172315 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
16.02.2017
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer.
Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy. Cell cycle distribution was measured by flow cytometry and immunofluorescence microscopy. Apoptosis and caspase-3 activity were measured by flow cytometry and fluorometric assay. Mice bearing flank anaplastic thyroid cancer (ATC) were treated with intraperitoneal injections of dinaciclib.
Dinaciclib inhibited thyroid cancer cell proliferation in a dose-dependent manner. Dinaciclib had a low median-effect dose (≤ 16.0 nM) to inhibit cell proliferation in seven thyroid cancer cell lines. Dinaciclib decreased CDK1, cyclin B1, and Aurora A expression, induced cell cycle arrest in the G2/M phase, and induced accumulation of prophase mitotic cells. Dinaciclib decreased Mcl-1, Bcl-xL and survivin expression, activated caspase-3 and induced apoptosis. In vivo, the growth of ATC xenograft tumors was retarded in a dose-dependent fashion with daily dinaciclib treatment. Higher-dose dinaciclib (50 mg/kg) caused slight, but significant weight loss, which was absent with lower-dose dinaciclib (40 mg/kg) treatment.
Dinaciclib inhibited thyroid cancer proliferation both in vitro and in vivo. These findings support dinaciclib as a potential drug for further studies in clinical trials for the treatment of patients with refractory thyroid cancer. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: PD Science, Inc., Paramus, New York, United States of America Competing Interests: The authors have declared that no competing interests exist. Conceptualization: SL.Data curation: SL.Formal analysis: SL.Funding acquisition: SL.Investigation: SL CH.Methodology: SL CH TC.Project administration: SL.Resources: JL RJW.Software: TC.Validation: TC RJW.Visualization: SL.Writing – original draft: SL.Writing – review & editing: JL CH TC RJW. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0172315 |