[Apoptosis of human leukemic cells induced by topoisomerase I and II inhibitors].
Comparison between five human leukemic lines (BV173, HL60, U937, K562, KCL22) suggest that the main determinant of their sensitivity to topoisomerase I (camptothecin) and II (VP-16) inhibitors is their ability to regulate cell cycle progression in response to specific DNA damage, then to die through apoptosis: the more the cells inhibit cell cycle progression, the less sensitive they are. The final pathway of apoptosis induction involves a cytoplasmic signal, active at neutral pH, needing magnesium, sensitive to various protease inhibitors and activated directly by staurosporine. Modulators of intracellular signaling (calcium chelators, calmodulin inhibitors, PKC modulators, kinase and phosphatase inhibitors) have no significant influence upon apoptosis induction. Conversely, apoptosis induction pathway is modified during monocytic differentiation of HL60 cells induced by phorbol esters. Lastly, poly(ADP-ribosyl)ation and chromatine structure should regulate apoptotic DNA fragmentation that is prevented by 3-aminobenzamide and spermine, respectively.
Solary
E
E
Laboratoire d'oncohématologie et pharmacologie, UFR de médecine/pharmacie, Dijon, France.
Dubrez
L
L
Eymin
B
B
Bertrand
R
R
Pommier
Y
Y
D000470:Alkaloids / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004273:DNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011493:Protein Kinase C; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D019311:Staurosporine; D002166:Camptothecin
Apoptose des cellules leucémiques humaines induite par les inhibiteurs de topo-isomérase I et II.