Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent

Maryanne C.S. Herzig, Alex V. Trevino, Huiyun Liang, Richard Salinas, Stephen J. Waters, John R. MacDonald, Barbara A. Woynarowska, Jan M. Woynarowski

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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 anti-apoptotic properties of Bcl-2 in HeLa cells with controlled Bcl-2 overexpression. Irofulven treatment resulted in rapid (12hr) dissipation of the mitochondrial membrane potential, phosphatidylserine externalization, and apoptotic DNA fragmentation, with progressive changes after 24hr. Bcl-2 overexpression caused marginal or partial inhibition of these effects after treatment times ranging from 12 to 48hr. 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.

Original languageEnglish (US)
Pages (from-to)503-513
Number of pages11
JournalBiochemical Pharmacology
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2003

Keywords

  • Apoptosis
  • Bcl-2 overexpression
  • Helenalin A
  • Irofulven
  • Mitochondria
  • Protein damage

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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    Herzig, M. C. S., Trevino, A. V., Liang, H., Salinas, R., Waters, S. J., MacDonald, J. R., Woynarowska, B. A., & Woynarowski, J. M. (2003). Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent. Biochemical Pharmacology, 65(4), 503-513. https://doi.org/10.1016/S0006-2952(02)01552-6