1. Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM.
- Author
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Liao, Jie, Hwang, Sung Hee, Li, Haonan, Yang, Yihe, Yang, Jun, Wecksler, Aaron T, Liu, Jun-Yan, Hammock, Bruce D, and Yang, Guang-Yu
- Subjects
Cell Line ,Tumor ,Animals ,Mice ,Inbred C57BL ,Mice ,Mutant Strains ,Carcinoma ,Pancreatic Ductal ,Pancreatic Neoplasms ,Genetic Predisposition to Disease ,Benzoates ,Urea ,Phenylurea Compounds ,Niacinamide ,Epoxide Hydrolases ,Proto-Oncogene Proteins c-raf ,Extracellular Signal-Regulated MAP Kinases ,Antineoplastic Agents ,Protein Kinase Inhibitors ,Tumor Burden ,Administration ,Oral ,Signal Transduction ,Cell Proliferation ,Phosphorylation ,Dose-Response Relationship ,Drug ,Phenotype ,Mutation ,Genes ,ras ,Male ,Oxylipins ,Sorafenib ,Growth inhibition ,Pancreatic carcinoma ,Soluble epoxide hydrolase ,c-Raf ,Pancreatic Cancer ,Rare Diseases ,Cancer ,Digestive Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - 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.
- Published
- 2016