Selective sensitization of transformed cells to flavopiridol-induced apoptosis following recruitment to S-phase.
Flavopiridol is a potent inhibitor of cyclin-dependent kinases (cdks). In a large proportion of solid tumor cell lines, the initial response to flavopiridol is cell cycle arrest. NCI-H661 non-small cell lung cancer cells are representative of a subset of more sensitive cell lines in which apoptosis is observed during the first 24 h of drug exposure. Analysis of the apoptotic population indicates that cells in S-phase are preferentially dying. In addition, cells are sensitized to flavopiridol following recruitment to S-phase, whether accomplished by synchronization or by treatment with noncytotoxic concentrations of chemotherapy agents that impose an S-phase delay. Combinations of gemcitabine or cisplatin, followed by flavopiridol at concentrations that correlate with cdk inhibition, produce sequence-dependent cytotoxic synergy. A survey of paired cell lines, including WI38 diploid fibroblasts or normal human bronchial epithelial cells, along with their SV40-transformed counterparts, demonstrates that treatment with flavopiridol during S-phase is selectively cytotoxic to transformed cells. These data suggest that treatment during S-phase may maximize responses to flavopiridol and that the administration of flavopiridol after chemotherapy agents that cause S-phase accumulation may be an efficacious antitumor strategy.
Matranga
Christian B
CB
Department of Adult Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Shapiro
Geoffrey I
GI
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000008:administration & dosage; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D003841:Deoxycytidine; C077990:alvocidib; D004247:DNA; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin; D000093542:Gemcitabine