PMID- 26683769 OWN - NLM STAT- MEDLINE DCOM- 20160614 LR - 20181202 IS - 1872-7980 (Electronic) IS - 0304-3835 (Print) IS - 0304-3835 (Linking) VI - 371 IP - 2 DP - 2016 Feb 28 TI - Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM. PG - 187-93 LID - S0304-3835(15)00732-6 [pii] LID - 10.1016/j.canlet.2015.11.042 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved. FAU - Liao, Jie AU - Liao J AD - Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: jie-liao@northwestern.edu. FAU - Hwang, Sung Hee AU - Hwang SH AD - Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA. FAU - Li, Haonan AU - Li H AD - Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. FAU - Yang, Yihe AU - Yang Y AD - Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. FAU - Yang, Jun AU - Yang J AD - Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA. FAU - Wecksler, Aaron T AU - Wecksler AT AD - Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA. FAU - Liu, Jun-Yan AU - Liu JY AD - Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA. FAU - Hammock, Bruce D AU - Hammock BD AD - Department of Entomology and Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA. FAU - Yang, Guang-Yu AU - Yang GY AD - Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: g-yang@northwestern.edu. LA - eng GR - R01CA172431/CA/NCI NIH HHS/United States GR - R01 CA164041/CA/NCI NIH HHS/United States GR - R01CA164041/CA/NCI NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - R01 CA172431/CA/NCI NIH HHS/United States GR - T32 CA108459/CA/NCI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20151209 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid) RN - 0 (Antineoplastic Agents) RN - 0 (Benzoates) RN - 0 (Oxylipins) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 0 (trans-4-(4-(3-(4-chloro-3-trifluoromethylphenyl)-ureido)-cyclohexyloxy-pyridine-2-carboxylic acid methylamide) RN - 25X51I8RD4 (Niacinamide) RN - 8W8T17847W (Urea) RN - 9ZOQ3TZI87 (Sorafenib) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - EC 3.3.2.10 (Ephx2 protein, mouse) SB - IM MH - Administration, Oral MH - Animals MH - Antineoplastic Agents/administration & dosage/pharmacokinetics/*pharmacology MH - Benzoates/pharmacokinetics/pharmacology MH - Carcinoma, Pancreatic Ductal/*drug therapy/enzymology/genetics/pathology MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - Dose-Response Relationship, Drug MH - Epoxide Hydrolases/*antagonists & inhibitors/metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - *Genes, ras MH - Genetic Predisposition to Disease MH - Male MH - Mice, Inbred C57BL MH - Mice, Mutant Strains MH - *Mutation MH - Niacinamide/administration & dosage/*analogs & derivatives/pharmacokinetics/pharmacology MH - Oxylipins/metabolism MH - Pancreatic Neoplasms/*drug therapy/enzymology/genetics/pathology MH - Phenotype MH - Phenylurea Compounds/administration & dosage/pharmacokinetics/*pharmacology MH - Phosphorylation MH - Protein Kinase Inhibitors/administration & dosage/pharmacokinetics/*pharmacology MH - Proto-Oncogene Proteins c-raf/*antagonists & inhibitors/metabolism MH - Signal Transduction/drug effects MH - Sorafenib MH - Tumor Burden/drug effects MH - Urea/analogs & derivatives/pharmacokinetics/pharmacology PMC - PMC4738175 MID - NIHMS743888 OTO - NOTNLM OT - Growth inhibition OT - Pancreatic carcinoma OT - Soluble epoxide hydrolase OT - c-Raf COIS- Conflict of interest statement None EDAT- 2015/12/20 06:00 MHDA- 2016/06/15 06:00 PMCR- 2017/02/28 CRDT- 2015/12/20 06:00 PHST- 2015/09/15 00:00 [received] PHST- 2015/11/28 00:00 [revised] PHST- 2015/11/30 00:00 [accepted] PHST- 2017/02/28 00:00 [pmc-release] PHST- 2015/12/20 06:00 [entrez] PHST- 2015/12/20 06:00 [pubmed] PHST- 2016/06/15 06:00 [medline] AID - S0304-3835(15)00732-6 [pii] AID - 10.1016/j.canlet.2015.11.042 [doi] PST - ppublish SO - Cancer Lett. 2016 Feb 28;371(2):187-93. doi: 10.1016/j.canlet.2015.11.042. Epub 2015 Dec 9.