title: Ibulocydine is a novel prodrug Cdk inhibitor that effectively induces apoptosis in hepatocellular carcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is frequently associated with abnormalities in cell cycle regulation, leading to increased activity of cyclin-dependent kinases (Cdks) due to the loss, or low expression of, Cdk inhibitors. In this study, we showed that ibulocydine (an isobutyrate prodrug of the specific Cdk inhibitor, BMK-Y101) is a candidate anti-cancer drug for HCC. Ibulocydine has high activity against Cdk7/cyclin H/Mat1 and Cdk9/cyclin T. Ibulocydine inhibited the growth of HCC cells more effectively than other Cdk inhibitors, including olomoucine and roscovitine, whereas ibulocydine as well as the other Cdk inhibitors and BMK-Y101 minimally influenced the growth of normal hepatocyte cells. Ibulocydine induced apoptosis in HCC cells, most likely by inhibiting Cdk7 and Cdk9. In vitro treatment of HCC cells with ibulocydine rapidly blocked phosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II, a process mediated by Cdk7/9. Anti-apoptotic gene products such as Mcl-1, survivin, and X-linked IAP (XIAP) are crucial for the survival of many cell types, including HCC. Following the inhibition of RNA polymerase II phosphorylation, ibulocydine caused rapid down-regulation of Mcl-1, survivin, and XIAP, thus inducing apoptosis. Furthermore, ibulocydine effectively induced apoptosis in HCC xenografts with no toxic side effects. These results suggest that ibulocydine is a strong candidate anti-cancer drug for the treatment of HCC.
authors.affiliation: Division of Pharmaceutical Biosciences, College of Pharmacy, The Research Institute for Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seung-Ju
authors.initials: SJ
authors.lastname: Cho
authors.forename: Young-Jong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: B Moon
authors.initials: BM
authors.lastname: Kim
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism
chemical_list: C559897:(5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo(2,3-d)pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; C559898:4-amino-6-bromo-1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-pyrrolo(2,3-d)pyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011741:Pyrimidine Nucleosides; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II