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


METHODS
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.


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.


CONCLUSIONS
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.
Wang
Weixin
W
Department of Surgery, University of Texas Health Science Center at San Antonio, 78229, USA.
Waters
Stephen J
SJ
MacDonald
John R
JR
Roth
Caleb
C
Shentu
Shujun
S
Freeman
James
J
Von Hoff
Daniel D
DD
Miller
Alexander R
AR
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D012717:Sesquiterpenes; C102714:irofulven; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one