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.