Inhibition of topoisomerase II by the marine alkaloid ascididemin and induction of apoptosis in leukemia cells

被引:66
作者
Dassonneville, L
Wattez, N
Baldeyrou, B
Mahieu, C
Lansiaux, A
Banaigs, B
Bonnard, I
Bailly, C
机构
[1] INSERM, Ctr Oscar Lambret, ICRL, U524, F-59045 Lille, France
[2] Ctr Oscar Lambret, Lab Pharmacol Antitumorale, F-59020 Lille, France
[3] Univ Perpignan, CNRS, UAR 461, Ctr Phytopharm, F-66860 Perpignan, France
关键词
ascididemin; topoisomerase; DNA cleavage; apoptosis; cell cycle; marine products; antitumor agent;
D O I
10.1016/S0006-2952(00)00351-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Ascididemin (ASC) is a pentacyclic DNA-intercalating agent isolated from the Mediterranean ascidian Cystodytes dellechiajei. This marine alkaloid exhibits marked cytotoxic activities against a range of tumor cells, but its mechanism of action remains poorly understood. We investigated the effects of ASC on DNA cleavage by human topoisomerases I and II. Relaxation assays using supercoiled DNA showed that ASC stimulated double-stranded cleavage of DNA by topoisomerase II, but exerted only a very weak effect on topoisomerase I. ASC is a conventional topoisomerase II poison that significantly promoted DNA cleavage, essentially at sites having a C on the 3' side of the cleaved bond (-1 position), as observed with etoposide. The stimulation of DNA cleavage by topoisomerase I in the presence of ASC was considerably weaker than that observed with camptothecin. Cytotoxicity measurements showed that: ASC was even less toxic to P388 leukemia cells than to P388CPT5 cells resistant to camptothecin. In addition, the marine alkaloid was found to be equally toxic to HL-60 leukemia cells sensitive or resistant to mitoxantrone. It is therefore unlikely that topoisomerases are the main cellular targets for ASC. This alkaloid was found to strongly induce apoptosis in HL-60 and P388 leukemia cells. Cell cycle analysis showed that ASC treatment was associated with a loss of cells in the G1 phase accompanied with a large increase in the sub-G1 region. Cleavage experiments with poly(ADP-ribose) polymerase (PARP) revealed that caspase-3 was a mediator of the apoptotic pathway induced by ASC. The DNA of ASC-treated cells was severely fragmented. Collectively, these findings indicate that ASC is a potent inducer of apoptosis in leukemia cells. BIOCHEM PHARMACOL 60;4:527-537, 2000. (C) 2000 Elsevier Science Inc.
引用
收藏
页码:527 / 537
页数:11
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