APOPTOSIS INDUCED BY DNA TOPOISOMERASE-I AND TOPOISOMERASE-II INHIBITORS IN HUMAN LEUKEMIC HL-60 CELLS

被引:90
作者
SOLARY, E [1 ]
BERTRAND, R [1 ]
POMMIER, Y [1 ]
机构
[1] UNIV MED,ONCOHEMATOL LAB,DIJON,FRANCE
关键词
HL-60; CELLS; APOPTOSIS; DNA TOPOISOMERASE INHIBITORS; ETOPOSIDE (VP-16); ADRIAMYCIN; CAMPTOTHECIN; LEUKEMIA; DNA DAMAGE; CELL CYCLE;
D O I
10.3109/10428199409051674
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 suppresser 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 macrophagelike 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.
引用
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页码:21 / 32
页数:12
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