期刊
BIOCHEMICAL PHARMACOLOGY
卷 65, 期 4, 页码 503-513出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(02)01552-6
关键词
irofulven; helenalin A; Bcl-2 overexpression; apoptotis; mitochondria; protein damage
资金
- NCI NIH HHS [CA 78706] Funding Source: Medline
The overexpression of Bcl-2 is implicated in the resistance of cancer cells to apoptosis. This study explored the potential of irofulven (hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863), a novel DNA- and protein-reactive anticancer drug, to overcome the antiapoptotic proper-ties of Bcl-2 in HeLa cells with controlled Bcl-2 overexpression, Irofulven treatment resulted in rapid (12 hr) dissipation of the mitochondrial membrane potential. phosphatidylserine externalization, and apoptotic DNA fragmentation, with progressive changes after 24 hr. Bcl-2 overexpression caused marginal or partial inhibition of these effects after treatment times ranging from 12 to 48 hr. Both Bcl-2-dependent and -independent responses to irofulven were abrogated by a broad-spectrum caspase inhibitor. Despite the somewhat decreased apoptotic indices. cell growth inhibition by irofulven was unaffected by Bcl-2 status. In comparison, Bcl-2 overexpression drastically reduced apoptotic DNA fragmentation by etoposide. acting via topoisomerase II-mediated DNA damage, but had no effect on apoptotic DNA fragmentation by helenalin A, which reacts with proteins but not DNA. Irofulven retains its pro-apoptotic and growth inhibitory potential in cell lines that have naturally high Bcl-2 expression. Collectively, the results implicate multiple mechanisms of apoptosis induction by irofulven, which may differ in time course and Bcl-2 dependence. It is possible that the sustained ability of irofulven to induce profound apoptosis and to block cell growth despite Bcl-2 overexpression may be related to its dual reactivity with both DNA and proteins. (C) 2002 Elsevier Science Inc. All rights reserved.
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