title: p21Waf1/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a camptothecin-selected human lung-cancer cell line.
abstract: The realization that chemotherapeutic agents induce apoptosis raises the concern that tumors resistant to chemotherapy are unable to initiate the apoptotic program. In the present study, we examined the apoptosis-resistance mechanism of a multidrug-resistant cell line, A549/CPT, which was established from the human lung-cancer cell line A549 by in vitro selection with gradually increased camptothecin (CPT) concentrations. We found that A549/CPT cells were resistant to anti-cancer drug-induced apoptosis in which caspase-3-like protease activity was attenuated remarkably, compared with parental A549 cells. We observed 2 mechanisms associated with apoptosis resistance in A549/CPT cells: over-expression of anti-apoptotic bcl-2 and elevated expression of p21Waf1/Cip1. Transfection of either bcl-2 or p21Waf1/Cip1 cDNA into parental A549 cells resulted in resistance to apoptosis. Furthermore, the co-treatment of p21Waf1/Cip1 and bcl-2 anti-sense oligodeoxy-nucleotides restored drug susceptibility in A549/CPT cells more effectively than either one of them alone. These results indicate that co-induction of bcl-2 and p21Waf1/Cip1 in A549/CPT cells may be involved in acquired drug resistance by inhibiting caspase-mediated apoptosis. Agents aimed at preventing both bcl-2 and p21Waf1/Cip1 expression may increase the efficiency of chemotherapy.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002166:Camptothecin / Q000633:toxicity*; D053148:Caspase 3; D061945:Caspase Inhibitors; D002945:Cisplatin / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000378:metabolism; D019254:Genes, bcl-2; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin; D002166:Camptothecin