title: Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM.
abstract: Mutant Kras and chronic pancreatitis are the most common pathological events involved in human pancreatic cancer. It has been demonstrated that c-Raf is responsible for transmitting signals from mutant Ras to its downstream signals including MEK-ERK and for initiating carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory and anti-pain epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the inhibition of mutant Kras(G12D)-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-Kras(G12D)/Pdx1-Cre mice and showed that t-CUPM significantly inhibited this murine pancreatic carcinoma cell growth both in vitro and in mice in vivo. Inhibition of mutant Kras-transmitted phosphorylations of cRAF/MEK/ERK was demonstrated in these pancreatic cancer cells using Western blot assay and immunohistochemical approach. Modulation of oxylipin profile, particularly increased EETs/DHET ratio by sEH inhibition, was observed in mice treated with t-CUPM. These results indicate that t-CUPM is a highly potential agent to treat pancreatic cancer via simultaneously targeting c-Raf and sEH.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: 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 95616, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yihe
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Wecksler
authors.affiliation: Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
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 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: g-yang@northwestern.edu.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001565:Benzoates / Q000493:pharmacokinetics / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D054883:Oxylipins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000970:Antineoplastic Agents; D001565:Benzoates; D054883:Oxylipins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C000595677:trans-4-(4-(3-(4-chloro-3-trifluoromethylphenyl)-ureido)-cyclohexyloxy-pyridine-2-carboxylic acid methylamide; D009536:Niacinamide; D014508:Urea; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: Growth inhibition; Pancreatic carcinoma; Soluble epoxide hydrolase; c-Raf