Inhibition of X-ray and doxorubicin-induced apoptosis by butyrolactone I, a CDK-specific inhibitor, in human tumor cells

Cell-cycle progression is coordinately regulated by cyclin-dependent kinase s (CDKs). The inhibition of CDKs by p21(Waf1/Cip1/Sdil) prevents the apopto sis of cells treated with DNA-damaging agents. In this study, we found that butyrolactone I, a specific inhibitor of CDC2 Family kinases, blocks the X -ray- or doxorubicin-induced apoptosis of DLD1 (p21+/+) human colorectal ca rcinoma cells in a dose-dependent manner. We also found that butyrolactone I inhibits the CDK2 activity and enhances cell survival after an X-ray irra diation or doxorubicin treatment in both DLD1 (p21-/-) and DLD1 (p21+/+) ce lls. These findings suggest that butyrolactone I prevents apoptosis by the direct inhibition of CDK and also, possibly, by CDK-inhibition through p53- independent p21-induction. Our findings indicate that CDK activity is requi red for DNA-damaging agent-induced apoptosis.