Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity.
We examined the effects of flavopiridol (FP), a cyclin-dependent kinase inhibitor, on doxorubicin (DOX)-induced cell killing in an osteosarcoma cell line (SaOs-2) that lacks functional retinoblastoma protein (pRb). The IC50 value for DOX was 7-fold lower when combined with a low dose (100 nM) FP in pRb-deficient SaOs-2 cells than in the absence of FP. In contrast, the IC50 value for DOX was not decreased in the presence of 100 nM FP in pRb-restored SaOs-2 cells. Consistent with this, FP enhanced DOX-induced activation of caspase-3, which correlates with apoptosis, in pRb-deficient cells but not in pRb-restored cells. Additional studies showed that FP decreased DOX-induced cell accumulation in S phase in retinoblastoma-restored cells but not in pRb-deficient cells. An increased expression of p21 and inhibition of cyclin-dependent kinase 2 kinase activity by FP was also observed in pRb-deficient cells but not in retinoblastoma-restored SaOs-2 cells. We conclude that pRb plays a key role in determining whether FP selectively sensitizes DOX-induced cell killing in human sarcoma cells. Because lack of functional pRb is a common abnormality in human cancers, the combination of FP with DOX in tumors lacking pRb would be worthy of further investigation.
Li
W
W
Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Fan
J
J
Bertino
J R
JR
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019925:Cyclin A / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000502:physiology; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D016160:Retinoblastoma Protein; C077990:alvocidib; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases