[Cisplatin resistance in a murine leukemia cell line associated with defect of apoptosis].
It has been recently reported that a number of anticancer drugs, including cisplatin, may exert their toxicity by inducing apoptosis. In order to investigate whether an alteration in the mechanisms involved in the process of apoptosis could contribute to cellular resistance, induction of apoptosis was studied in a cisplatin-resistant cell line (L1210/DDP) derived from a L1210 murine leukemia cell line (L1210/0). We first established that the mutant cell line resisted 5-azacytidine, a drug to which it was never exposed and which is known to have a very different mechanism of action from that of cisplatin. We then showed that these cells did not exhibit any DNA fragmentation or morphological changes typical of apoptosis, when exposed to toxic concentrations of either cisplatin or 5-azacytidine. The failure of these cells to undergo typical apoptosis upon cisplatin or 5-azacytidine exposure was correlated with the lack of a nuclear endonuclease activity present in wild type cell nuclei. However, staurosporine, a potent protein kinase C inhibitor, which exerted the same toxicity on both cell lines, induced the internucleosomal DNA fragmentation and morphological features of apoptosis in both of them. This indicates that a functional pathway for apoptosis is preserved in the resistant cells. The induction of this pathway can be correlated with the presence of a cytoplamic endonuclease activity whose specificity seems different from that operating in L1210/0 cells. In conclusion, our data indicate that the mechanisms which control activation of apoptosis in L1210/0 cells differ from those which operate in L1210/DDP cells. One of the differences concerns the nature and the subcellular localization of the endonuclease activity possibly involved in the internucleosomal DNA cleavage.
Segal-Bendirdjian
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Unité de physicochimie et pharmacologie des macromolécules biologiques (URA147), Villejuif, France.
Jacquemin-Sablon
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A
D000470:Alkaloids / Q000633:toxicity; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism; D007939:Leukemia L1210 / Q000473:pathology*; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D011493:Protein Kinase C; D004720:Endonucleases; D019311:Staurosporine; D001374:Azacitidine; D002945:Cisplatin
Résistance au cisplatine d'une lignée de leucémie murine associée à un défaut d'apoptose.