Article

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

Department of Surgery, University of Texas Health Science Center at San Antonio, 78229, USA.
Anticancer research (Impact Factor: 1.87). 01/2002; 22(2A):559-64.
Source: PubMed

ABSTRACT 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.
Westem blot analysis and kinase assays were used to demonstrate the activation of Erk 1/2 and JNK1 kinases following Irofulven administration in the presence and absence of selective kinase inhibitors.
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.
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.

0 Bookmarks
 · 
168 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported that 15-deoxy-delta-prostaglandin J2 (15d-PGJ2), a potent ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induces caspase-mediated apoptosis in human pancreatic cancer cell lines. Mitogen-activated protein kinases (MAPKs) are known to regulate apoptosis in various cancers. The purpose of this study was to investigate the role of MAPKs (ERK, JNK, and p38) in 15d-PGJ2-induced pancreatic cancer cell apoptosis. The effect of 15d-PGJ2 on MAPK activity was investigated by kinase assays using the human pancreatic cancer cell line MIA PaCa-2. Western blot analysis was performed to analyze phosphorylation of MAPKs, activation of caspases and poly ADP-ribose polymerase (PARP) cleavage. Apoptosis was evaluated by caspase-3 enzymatic activity and DNA fragmentation assay. 15d-PGJ2 activated all 3 MAPKs in a dose- and time-dependent fashion. SB202190, an inhibitor of p38, prevented 15d-PGJ2-induced activation of caspase-8, -9, and -3 and significantly decreased apoptosis. This effect was potentiated by SP600125, an inhibitor of JNK, although SP600125 alone had no significant effect on 15d-PGJ2-induced apoptosis. In contrast, PD98059, an inhibitor of MEK, significantly increased sensitivity to 15d-PGJ2-induced apoptosis. 15d-PGJ2 stimulates proapoptotic and antiapoptotic MAPK pathways. Sensitivity to 15d-PGJ2-induced apoptosis is increased by ERK inhibition but decreased by inhibition of p38.
    Pancreas 04/2004; 28(2):153-9. · 3.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Death from pancreatic cancer remains high with few long-term survivors. Systemic chemotherapy with 5-fluorouracil-based combinations had minimal impact on natural history of this disease. Several new agents with activity against pancreatic cancer have been identified over the past decade. Gemcitabine has modest activity in this disease. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan show improved outcomes in objective response rates and survival that need to be confirmed in prospectively randomized studies. Advancement in the understanding of the biology of pancreatic cancer has helped identify several molecular targets for the development of novel therapies. Ongoing and future treatment regimens for pancreatic cancer will incorporate traditional cytotoxic drugs and novel targeted therapies.
    Expert Review of Anti-infective Therapy 09/2002; 2(4):426-36. · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Once thought to be a relatively untreatable disease, pancreatic cancer has recently become a focus of intense clinical research. The systemic administration of gemcitabine (Gemzar) is currently considered the standard first-line treatment for patients with advanced disease. While treatment with gemcitabine has been shown to result in both clinical benefit and prolongation of survival, objective tumor responses are relatively uncommon and median survival times remain short. Several recent efforts have therefore focused on evaluating chemotherapy regimens in which gemcitabine is combined with other cytotoxic drugs. While randomized trials have now confirmed that such combinations are associated with higher response rates, they have not yet clearly demonstrated that combination therapy results in a survival advantage. Increasingly, attention has turned to a number of novel chemotherapeutic and biologic agents that appear promising and are likely to play an important future role in the treatment of patients with this disease.
    Expert Review of Anti-infective Therapy 11/2003; 3(5):729-39. · 2.28 Impact Factor