Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

0421049 - ÚEB 2014 RIV US eng J - Journal Article
Haider, C. - Grubinger, M. - Řezníčková, Eva - Weiss, T.S. - Rotheneder, H. - Miklos, W. - Berger, W. - Jorda, Radek - Zatloukal, M. - Gucký, T. - Strnad, Miroslav - Kryštof, Vladimír - Mikulits, W.
Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance.
Molecular Cancer Therapeutics. Roč. 12, č. 10 (2013), s. 1947-1957. ISSN 1535-7163. E-ISSN 1538-8514
R&D Projects: GA ČR GAP305/12/0783; GA ČR GA301/08/1649
Institutional research plan: CEZ:AV0Z50380511
Keywords : PRIMARY HUMAN HEPATOCYTES * SELICICLIB R-ROSCOVITINE * CELL-CYCLE
Subject RIV: CE - Biochemistry
Impact factor: 6.107, year: 2013

Treatment options for hepatocellular carcinoma using chemotherapeutics at intermediate and advanced stages of disease are limited as patients most rapidly escape from therapy and succumb to disease progression. Mechanisms of the hepatic xenobiotic metabolism are mostly involved in providing chemoresistance to therapeutic compounds. Given the fact that the aberrant activation of cyclin-dependent kinases (CDK) is frequently observed in hepatocellular carcinomas, we focused on the efficacy of the novel compounds BA-12 and BP-14 that antagonize CDK1/2/5/7 and CDK9. Inhibition of those CDKs in human hepatocellular carcinoma cell lines reduced the clonogenicity by arresting cells in S-G(2) and G(2)-M phase of the cell cycle and inducing apoptosis. In contrast, primary human hepatocytes failed to show cytotoxicity and apoptosis. No loss of chemosensitivity was observed in hepatocellular carcinoma cells after long-term exposure to inhibitors. In vivo, treatment of xenografted human hepatocellular carcinomas with BA-12 or BP-14 effectively repressed tumor formation. Moreover, BA-12 or BP-14 significantly diminished diethylnitrosamine (DEN)-induced hepatoma development in mice. These data show that BA-12 or BP-14 exhibit strong antitumorigenic effects in the absence of chemoresistance, resulting in a superior efficacy compared with currently used chemotherapeutics in hepatocellular carcinomas.
Permanent Link: http://hdl.handle.net/11104/0227508