From molecular characteristics to cellular events in apoptosis-resistant HL-60 cells.
The ability to induce apoptosis in tumor cells is critical to elicit a positive response to cytotoxic chemo-therapy. In this study, we investigated the effect of the topoisomerase I inhibitors camptothecin and SN-38, known to cause an unusual form of DNA damage, on apoptotic pathways using the leukemic cell line HL-60 and its vincristine-resistant variant HL-60 VCR. Both camptothecin and SN-38 induced high levels of apoptosis in sensitive cells when compared to the multidrug-resistant ones. Interestingly, a higher BCL-2/BAX ratio was observed in HL-60 VCR at the basal state and during treatments. Moreover, these cells which did not exhibit Bcr-abl translocation or bcrp efflux pump, overexpressed topoisomerase I protein. The data provide evidence that BCL-2 protein could protect HL-60 VCR from mitochondrial membrane depolarization and block ROS production in these cells. Finally, our results suggest that dysregulation of proteins associated with DNA replication and apoptotic process could contribute to the multidrug-resistance phenotype.
Palissot
Valérie
V
Laboratoire d'Hémato-Cancérologie Expérimentale, Centre Hospitalier de Luxembourg, L-1210 Luxembourg. valerie.palissot@crp-sante.healthnet.lu
Morjani
Hamid
H
Belloc
Francis
F
Cotteret
Sophie
S
Dufer
Jean
J
Berchem
Guy
G
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004249:DNA Damage; D004261:DNA Replication; D018432:Drug Resistance, Multiple; D018922:HL-60 Cells; D006801:Humans; D000077146:Irinotecan; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051562:Proto-Oncogene Proteins c-bcr; D014178:Translocation, Genetic
D000972:Antineoplastic Agents, Phytogenic; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077146:Irinotecan; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D002166:Camptothecin