Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance.

Abstract

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-G2 and G2-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.

• Authors: Christine Haider, Markus Grubinger, Eva Řezníčková, Thomas S Weiss, Hans Rotheneder, Walter Miklos, Walter Berger, Radek Jorda, Marek Zatloukal, Tomáš Gucky, Miroslav Strnad, Vladimír Kryštof, Wolfgang Mikulits
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 10 Pg. 1947-57 (Oct 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23939380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• 2-(((2-((4-aminocyclohexyl)amino)-9-cyclopentylpurin-6-yl)amino)methyl)-4-chlorophenol
• N2-(4-aminocyclohexyl)-9-cyclopentyl-N6-((6-(2-furyl)-3-pyridyl)methyl)purine-2,6-diamine
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• Diethylnitrosamine
• 2-Aminopurine
• Cyclin-Dependent Kinases

Topics

• 2-Aminopurine (administration & dosage, analogs & derivatives)
• Animals
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (chemically induced, drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Diethylnitrosamine (toxicity)
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (chemically induced, drug therapy, pathology)
• Mice
• Primary Cell Culture
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays