Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM

Jie Liao, Sung Hee Hwang, Haonan Li, Yihe Yang, Jun Yang, Aaron T. Wecksler, Jun Yan Liu, Bruce D. Hammock, Guang Yu Yang

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 KrasG12D-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-KrasG12D/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.

Original languageEnglish (US)
Pages (from-to)187-193
Number of pages7
JournalCancer Letters
Volume371
Issue number2
DOIs
StatePublished - 2016

Fingerprint

Epoxide Hydrolases
Pancreatic Neoplasms
Mitogen-Activated Protein Kinase Kinases
Growth
Oxylipins
Proto-Oncogene Proteins c-raf
Chronic Pancreatitis
Carcinogenesis
Anti-Inflammatory Agents
Pharmacokinetics
Western Blotting
Phosphorylation
Pain
Acids
Pancreatic Carcinoma
Inhibition (Psychology)
Enzymes
sorafenib

Keywords

  • C-Raf
  • Growth inhibition
  • Pancreatic carcinoma
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM. / Liao, Jie; Hwang, Sung Hee; Li, Haonan; Yang, Yihe; Yang, Jun; Wecksler, Aaron T.; Liu, Jun Yan; Hammock, Bruce D.; Yang, Guang Yu.

In: Cancer Letters, Vol. 371, No. 2, 2016, p. 187-193.

Research output: Contribution to journalArticle

Liao, J, Hwang, SH, Li, H, Yang, Y, Yang, J, Wecksler, AT, Liu, JY, Hammock, BD & Yang, GY 2016, 'Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM', Cancer Letters, vol. 371, no. 2, pp. 187-193. https://doi.org/10.1016/j.canlet.2015.11.042
Liao, Jie ; Hwang, Sung Hee ; Li, Haonan ; Yang, Yihe ; Yang, Jun ; Wecksler, Aaron T. ; Liu, Jun Yan ; Hammock, Bruce D. ; Yang, Guang Yu. / Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM. In: Cancer Letters. 2016 ; Vol. 371, No. 2. pp. 187-193.
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AU - Wecksler, Aaron T.

AU - Liu, Jun Yan

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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 KrasG12D-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-KrasG12D/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.

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