Irofulven (6-hydroxymethylacylfulvene, MGI 114)-induced apoptosis in human pancreatic cancer cells is mediated by ERK and JNK kinases

Weixin Wang, Stephen J. Waters, John R. MacDonald, Caleb Roth, Shujun Shentu, James Freeman, Daniel D. Von Hoff, Alexander R. Miller

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Background: Pancreatic carcinoma resists chemotherapeutic mediation of apoptosis. Irofulven (MGI 114, 6-hydroxymethylacylfulvene) is a novel illudin S analogue that we have shown to induce caspase-mediated apoptosis in pancreatic carcinoma cell lines. Materials and Methods: Western blot analysis and kinase assays were used to demonstrate the activation of Erk 1/2 and JNK 1 kinases following Irofulven administration in the presence and absence of selective kinase inhibitors. Results: Irofulven activates JNK1 and Erk1/2, but not p38. The addition of the MAPK inhibitors, SB202190 and PD98059 (targeting JNK1 and Erk1/2 activation, respectively), prevents kinase activation and blocks Irofulven-induced activation of caspases -3, -7, -8 and -9. Blockade of either JNK1 or Erk1/2 results in a 50% decrease in apoptosis in MiaPaCa-2 cells treated with Irofulven. Conclusion: Our data demonstrated that JNK1 and Erk1/2 are activated by Irofulven treatment and that blockade of either MAPK subfamily decreases apoptosis by rendering Irofulven incapable of inducing caspase activation.

Original languageEnglish (US)
Pages (from-to)559-564
Number of pages6
JournalAnticancer Research
Volume22
Issue number2 A
StatePublished - May 16 2002

Keywords

  • Apoptosis
  • Caspase
  • Irofulven
  • MAPK

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Irofulven (6-hydroxymethylacylfulvene, MGI 114)-induced apoptosis in human pancreatic cancer cells is mediated by ERK and JNK kinases'. Together they form a unique fingerprint.

  • Cite this

    Wang, W., Waters, S. J., MacDonald, J. R., Roth, C., Shentu, S., Freeman, J., Von Hoff, D. D., & Miller, A. R. (2002). Irofulven (6-hydroxymethylacylfulvene, MGI 114)-induced apoptosis in human pancreatic cancer cells is mediated by ERK and JNK kinases. Anticancer Research, 22(2 A), 559-564.