Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM. Issue 2 (28th February 2016)

• Record Type: Journal Article
• Authors: Liao, Jie; Hwang, Sung Hee; Li, Haonan; Yang, Yihe; Yang, Jun; Wecksler, Aaron T.; Liu, Jun-Yan; Hammock, Bruce D.; Yang, Guang-Yu
• Is Part Of: Cancer letters. Volume 371:Issue 2(2016)
• Page Start: 187
• Page End: 193
• Publication Date: 2016-02-28
• Subjects: Pancreatic carcinoma -- c-Raf -- Soluble epoxide hydrolase -- Growth inhibition; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.11.042
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlight: Findings demonstrated a newly synthesized compound, t- CUPM, was a dual small molecule inhibitor of c-Raf and proinflammatory enzyme soluble epoxide hydrolase and had high potential for inhibiting Kras-initiated 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.