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Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma

Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expressio...

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Autores principales: Shao, Yu-Yun, Li, Yong-Shi, Hsu, Hung-Wei, Lin, Hang, Wang, Han-Yu, Wo, Rita Robin, Cheng, Ann-Lii, Hsu, Chih-Hung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827105/
https://www.ncbi.nlm.nih.gov/pubmed/31561409
http://dx.doi.org/10.3390/cancers11101433
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author Shao, Yu-Yun
Li, Yong-Shi
Hsu, Hung-Wei
Lin, Hang
Wang, Han-Yu
Wo, Rita Robin
Cheng, Ann-Lii
Hsu, Chih-Hung
author_facet Shao, Yu-Yun
Li, Yong-Shi
Hsu, Hung-Wei
Lin, Hang
Wang, Han-Yu
Wo, Rita Robin
Cheng, Ann-Lii
Hsu, Chih-Hung
author_sort Shao, Yu-Yun
collection PubMed
description Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expression levels. Dinaciclib significantly downregulated the phosphorylation of Rb (target of CDKs 1 and 2), ataxia telangiectasia mutated kinase (target of CDK5), and RNA polymerase II (target of CDK9) in the HCC cells. In xenograft studies, mice receiving dinaciclib tolerated the treatment well without significant body weight changes and exhibited a significantly slower tumor growth rate than the mice receiving vehicles. RNA interference (RNAi) of CDKs 1 and 9 was more effective in inhibiting the cell proliferation of HCC cells than RNAi of CDKs 2 and 5. Overexpression of CDK9 significantly reduced the efficacy of dinaciclib in HCC cells, but overexpression of CDK1 did not. In conclusion, composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib exhibited potent in vitro and in vivo activity against HCC. CDK9 inhibition might be the crucial mechanism.
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spelling pubmed-68271052019-11-18 Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma Shao, Yu-Yun Li, Yong-Shi Hsu, Hung-Wei Lin, Hang Wang, Han-Yu Wo, Rita Robin Cheng, Ann-Lii Hsu, Chih-Hung Cancers (Basel) Article Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expression levels. Dinaciclib significantly downregulated the phosphorylation of Rb (target of CDKs 1 and 2), ataxia telangiectasia mutated kinase (target of CDK5), and RNA polymerase II (target of CDK9) in the HCC cells. In xenograft studies, mice receiving dinaciclib tolerated the treatment well without significant body weight changes and exhibited a significantly slower tumor growth rate than the mice receiving vehicles. RNA interference (RNAi) of CDKs 1 and 9 was more effective in inhibiting the cell proliferation of HCC cells than RNAi of CDKs 2 and 5. Overexpression of CDK9 significantly reduced the efficacy of dinaciclib in HCC cells, but overexpression of CDK1 did not. In conclusion, composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib exhibited potent in vitro and in vivo activity against HCC. CDK9 inhibition might be the crucial mechanism. MDPI 2019-09-26 /pmc/articles/PMC6827105/ /pubmed/31561409 http://dx.doi.org/10.3390/cancers11101433 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shao, Yu-Yun
Li, Yong-Shi
Hsu, Hung-Wei
Lin, Hang
Wang, Han-Yu
Wo, Rita Robin
Cheng, Ann-Lii
Hsu, Chih-Hung
Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title_full Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title_fullStr Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title_full_unstemmed Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title_short Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma
title_sort potent activity of composite cyclin dependent kinase inhibition against hepatocellular carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827105/
https://www.ncbi.nlm.nih.gov/pubmed/31561409
http://dx.doi.org/10.3390/cancers11101433
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