Involvement of cyclin-dependent kinases in doxorubicin-induced apoptosis in human tumor cells

Apoptotic cell death caused by doxorubicin, a chemotherapeutic agent, is su ppressed by expression of p21 (waf1/ cip1/sdi1), a cyclin-dependent kinase (cdk) inhibitor. To examine cdk activity required for doxorubicin-induced a poptosis, we transfected p21-deficient human tumor DLD1 (p21-/-) cells with plasmids carrying wild-type p21 and mutated p21 unable to bind to cdks or proliferating cell nuclear antigen. The apoptosis induced at the G(2)/M pha se after doxorubicin treatment was suppressed by transient expression of th e p21 with cdk-binding activity but not by the p21 lacking the activity. We also transfected cells with plasmids carrying wild-type, dominant negative and constitutively active mutants of cdk2 or cdk4. The apoptosis was suppr essed by transient expression of dominant negative mutants of cdk2 or cdk4. These findings indicate that cdk is involved in the doxorubicin-induced ap optosis pathway. Mel. Carcinog. 29. 1-7, 2000. (C) 2000 Wiley-Liss. Inc.