Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL-60 cells.
The induction of apoptosis following topoisomerase inhibitors proceeds in at least three distinct steps: (1) induction of cleavable complexes (potentially lethal damage), (2) topoisomerase-induced DNA damage, and (3) a presently unknown sequence of events that must either lead to cell cycle arrest (G2-block, differentiation) or apoptosis. DNA degradation provides a convenient way to quantify apoptosis in HL-60 cells. Extensive apoptosis can be induced rapidly in undifferentiated HL-60 cells without prevention by cycloheximide or actinomycin D. Therefore, HL-60 cells appear to express constitutively the apoptotic machinery that may be kept under control of a yet unknown repressor. The absence of the tumor suppressor p53 and the presence of bcl-2 are in contrast with the sensitivity of these cells to apoptosis. Agents that modify chromatin structure (zinc, poly[ADPribose] inhibitors, spermine) can block DNA fragmentation without affecting cell survival. By contrast macrophage-like differentiation by phorbol esters suppresses apoptosis without affecting topoisomerase-induced DNA damage. Better understanding of the apoptotic regulation in the widely used and characterized HL-60 cell line should allow the identification of new mechanisms and parameters of cellular sensitivity and resistance to the cytotoxic activity of anticancer agents.
Laboratory of Oncohematology, University of Medicine, Dijon, France.
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E
Solary
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Bertrand
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Pommier
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D002843:Chromatin; D004273:DNA, Neoplasm; D005938:Glucocorticoids; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II