title: Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG¹²D/Pdx-1-Cre Mice.
abstract: Mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. In the process of long-standing chronic inflammation, aberrant metabolites of arachidonic acid play a crucial role in promoting carcinogenesis, in which the soluble epoxide hydrolase (sEH), as a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we determined the effect of our newly-synthesized novel compound trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM), a dual inhibitor of sEH and RAF1 proto-oncogene serine/threonine kinase (c-RAF), on inhibiting the development of pancreatitis and pancreatic intraepithelial neoplasia (mPanIN) in LSL-Kras(G12D)/Pdx1-Cre mice. The results showed that t-CUPM significantly reduced the severity of chronic pancreatitis, as measured by the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high-grade mPanIN II/III was significantly suppressed. Inhibition of mutant Kras-transmitted phosphorylation of mitogen-activated protein kinase's kinase/extracellular signal-regulated kinases was demonstrated in pancreatic tissues by western blots. Quantitative real-time polymerase chain reaction analysis revealed that t-CUPM treatment significantly reduced the levels of inflammatory cytokines including tumor necrosis facor-α, monocyte chemoattractant protein-1, as well as vascular adhesion molecule-1, and the levels of Sonic hedgehog and Gli transcription factor (Hedgehog pathway). Analysis of the eicosanoid profile revealed a significant increase of the EETs/dihydroxyeicosatrienoic acids ratio, which further confirmed sEH inhibition by t-CUPM. These results indicate that simultaneous inhibition of sEH and c-RAF by t-CUPM is important in preventing chronic pancreatitis and carcinogenesis.
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL, U.S.A. g-yang@northwestern.edu jie-liao@northwestern.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA, U.S.A.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL, U.S.A.
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA, U.S.A.
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA, U.S.A.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL, U.S.A. g-yang@northwestern.edu jie-liao@northwestern.edu.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002278:Carcinoma in Situ / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002108:Ceruletide; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D019426:Integrases / Q000235:genetics* / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation; D060787:Neoplasm Grading; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D050500:Pancreatitis, Chronic / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D000090063:Proto-Oncogene Mas; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C000595677:trans-4-(4-(3-(4-chloro-3-trifluoromethylphenyl)-ureido)-cyclohexyloxy-pyridine-2-carboxylic acid methylamide; D009536:Niacinamide; D002108:Ceruletide; C045073:Cre recombinase; D019426:Integrases; D004851:Epoxide Hydrolases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: c-RAF; carcinogenesis; chemoprevention; pancreatitis; soluble epoxide hydrolase