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 Citations (Scopus)

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

Fingerprint

Antineoplastic Agents
Apoptosis
DNA
Proteins
DNA Fragmentation
Cell growth
Growth
Cells
Type II DNA Topoisomerase
Caspase Inhibitors
irofulven
Mitochondrial Membrane Potential
Phosphatidylserines
Etoposide
HeLa Cells
DNA Damage
Membranes
Cell Line
Pharmaceutical Preparations
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Herzig, M. C. S., Trevino, A. V., Liang, H., Salinas, R., Waters, S. J., MacDonald, J. R., ... 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

Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent. / Herzig, Maryanne C S; Trevino, Alex V.; Liang, Huiyun; Salinas, Richard; Waters, Stephen J.; MacDonald, John R.; Woynarowska, Barbara A.; Woynarowski, Jan M.

In: Biochemical Pharmacology, Vol. 65, No. 4, 15.02.2003, p. 503-513.

Research output: Contribution to journalArticle

Herzig, MCS, Trevino, AV, Liang, H, Salinas, R, Waters, SJ, MacDonald, JR, Woynarowska, BA & Woynarowski, JM 2003, 'Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent', Biochemical Pharmacology, vol. 65, no. 4, pp. 503-513. https://doi.org/10.1016/S0006-2952(02)01552-6
Herzig, Maryanne C S ; Trevino, Alex V. ; Liang, Huiyun ; Salinas, Richard ; Waters, Stephen J. ; MacDonald, John R. ; Woynarowska, Barbara A. ; Woynarowski, Jan M. / Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent. In: Biochemical Pharmacology. 2003 ; Vol. 65, No. 4. pp. 503-513.
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