Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma

• Main Authors: Yu-Yun Shao, Yong-Shi Li, Hung-Wei Hsu, Hang Lin, Han-Yu Wang, Rita Robin Wo, Ann-Lii Cheng, Chih-Hung Hsu
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: Cancers
• Subjects: cell cycle; cyclin-dependent kinase; dinaciclib; hepatocellular carcinoma
• Online Access: https://www.mdpi.com/2072-6694/11/10/1433

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.