Alteration in p53 pathway and defect in apoptosis contribute independently to cisplatin-resistance.
The accumulation of molecular genetic defects selected during the adaptation process in the development of cisplatin-resistance was studied using progressive cisplatin-resistant variants (L1210/DDP2, L1210/DDP5, L1210/DDP10) derived from a murine leukemia cell line (L1210/0). Of these cell lines, only the most resistant L1210/DDP10 was cross-resistant to etoposide and deficient in apoptosis induced by these two drugs, indicating that resistance to DNA-damaging agents correlates with a defect in apoptosis. This defect was tightly associated with the loss of a Ca2+/Mg2+-dependent nuclear endonuclease activity present in the less cisplatin-resistant cells. Evidence is presented that p53-dependent function (a) is lost not only in the apoptosis defective L1210/DDP10 cells, but also in the apoptosis susceptible L1210/DDP5 cells; (b) is unrelated to drug-induced cell cycle perturbations. These results suggest that deficiency in the p53 pathway and resistance to DNA-damaging agents due to a defect in apoptosis are independent events.
Ségal-Bendirdjian
E
E
Unité de Physicochimie et Pharmacologie des Macromolécules Biologiques (CNRS, URA 147), Institut Gustave-Roussy, rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Mannone
L
L
Jacquemin-Sablon
A
A
D000818:Animals; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics*; D004720:Endonucleases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D017304:Annexin A5; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004720:Endonucleases; D019311:Staurosporine; D016650:Fluorescein-5-isothiocyanate; D002945:Cisplatin