Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance.
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.
Corresponding Author: Wolfgang Mikulits, Medical University Vienna, Borschkegasse 8a, Vienna 1090, Austria. wolfgang.mikulits@meduniwien.ac.at.
Christine
C
Haider
Markus
M
Grubinger
Eva
E
Řezníčková
Thomas S
TS
Weiss
Hans
H
Rotheneder
Walter
W
Miklos
Walter
W
Berger
Radek
R
Jorda
Marek
M
Zatloukal
Tomáš
T
Gucky
Miroslav
M
Strnad
Vladimír
V
Kryštof
Wolfgang
W
Mikulits
D015075:2-Aminopurine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004052:Diethylnitrosamine / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C588397:2-(((2-((4-aminocyclohexyl)amino)-9-cyclopentylpurin-6-yl)amino)methyl)-4-chlorophenol; C588398:N2-(4-aminocyclohexyl)-9-cyclopentyl-N6-((6-(2-furyl)-3-pyridyl)methyl)purine-2,6-diamine; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine; D015075:2-Aminopurine; D018844:Cyclin-Dependent Kinases