Number of the records: 1
Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance
- 1.
SYSNO ASEP 0421049 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance Author(s) Haider, C. (AT)
Grubinger, M. (AT)
Řezníčková, Eva (UEB-Q) RID, ORCID
Weiss, T.S. (DE)
Rotheneder, H. (AT)
Miklos, W. (AT)
Berger, W. (AT)
Jorda, Radek (UEB-Q) ORCID, RID
Zatloukal, M. (CZ)
Gucký, T. (CZ)
Strnad, Miroslav (UEB-Q) RID, ORCID
Kryštof, Vladimír (UEB-Q) RID, ORCID
Mikulits, W. (AT)Source Title Molecular Cancer Therapeutics. - : American Association for Cancer Research - ISSN 1535-7163
Roč. 12, č. 10 (2013), s. 1947-1957Number of pages 11 s. Language eng - English Country US - United States Keywords PRIMARY HUMAN HEPATOCYTES ; SELICICLIB R-ROSCOVITINE ; CELL-CYCLE Subject RIV CE - Biochemistry R&D Projects GAP305/12/0783 GA ČR - Czech Science Foundation (CSF) GA301/08/1649 GA ČR - Czech Science Foundation (CSF) CEZ AV0Z50380511 - UEB-Q (2005-2011) UT WOS 000325548400003 DOI 10.1158/1535-7163.MCT-13-0263 Annotation 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2014
Number of the records: 1