Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo

Jun Yan Liu, See Hyoung Park, Christophe Morisseau, Hee Hwang Sung, Bruce D. Hammock, Robert H Weiss

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The advent of multikinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor has revolutionized the treatment of highly angiogenic malignancies such as renal cell carcinoma. Interestingly, several such inhibitors are commercially available, and they each possess diverse specific beneficial and adverse effect profiles. In examining the structure of sorafenib, it was hypothesized that this compound would possess inhibitory effects on the soluble epoxide hydrolase, an enzyme with pleiotropic effects on inflammation and vascular disease. We now show that sorafenib but not another VEGF receptor targeted inhibitor sunitinib is a potent inhibitor of the human soluble epoxide hydrolase in vitro (KI = 17 ± 4 nmol/L). Furthermore, sorafenib causes the expected in vivo shift in oxylipid profile resulting from soluble epoxide hydrolase inhibition, evidence of a reduction in the acute inflammatory response. Lipopolysaccharide-induced hypotension was reversed with sorafenib but not sunitinib treatment, suggesting that soluble epoxide hydrolase inhibition accounts for at least part of the anti-inflammatory effect of sorafenib. The pharmacokinetic studies presented here in light of the known potency of sorafenib as a soluble epoxide hydrolase inhibitor indicate that the soluble epoxide hydrolase will be largely inhibited at therapeutic doses of sorafenib. Thus, it is likely that soluble epoxide hydrolase inhibition contributes to the beneficial effects from the inhibition of the VEGF receptor and other kinases during treatment with sorafenib.

Original languageEnglish (US)
Pages (from-to)2193-2203
Number of pages11
JournalMolecular Cancer Therapeutics
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2009

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Epoxide Hydrolases
Vascular Endothelial Growth Factor Receptor
Controlled Hypotension
sorafenib
Vascular Diseases
Renal Cell Carcinoma
Lipopolysaccharides
Anti-Inflammatory Agents
Phosphotransferases
Pharmacokinetics
Inflammation
Enzymes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo. / Liu, Jun Yan; Park, See Hyoung; Morisseau, Christophe; Sung, Hee Hwang; Hammock, Bruce D.; Weiss, Robert H.

In: Molecular Cancer Therapeutics, Vol. 8, No. 8, 01.08.2009, p. 2193-2203.

Research output: Contribution to journalArticle

Liu, Jun Yan ; Park, See Hyoung ; Morisseau, Christophe ; Sung, Hee Hwang ; Hammock, Bruce D. ; Weiss, Robert H. / Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 8. pp. 2193-2203.
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