YU-YUN SHAOYong-Shi LiHung-Wei HsuHang LinHan-Yu WangRita Robin WoANN-LII CHENGCHIH-HUNG HSU2020-04-092020-04-0920192072-6694https://scholars.lib.ntu.edu.tw/handle/123456789/484012© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the effcacy 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 effcacy 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.Cell cycle | Cyclin-dependent kinase | Dinaciclib | Hepatocellular carcinomaCell cycle; Cyclin-dependent kinase; Dinaciclib; Hepatocellular carcinoma[SDGs]SDG3ATM protein; cyclin dependent kinase 1; cyclin dependent kinase 2; cyclin dependent kinase 5; cyclin dependent kinase 9; dinaciclib; Myc protein; retinoblastoma protein; RNA polymerase II; animal experiment; animal model; animal tissue; antineoplastic activity; antiproliferative activity; Article; cancer chemotherapy; cancer inhibition; controlled study; drug efficacy; drug mechanism; drug potency; drug tolerability; enzyme inhibition; in vitro study; in vivo study; liver cell carcinoma; mouse; nonhuman; protein expression; protein phosphorylationjournal article10.3390/cancers11101433622352472-s2.0-85073460390https://doi.org/10.3390/cancers1110143362235247