title: Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis.
abstract: Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg · kg(-1) · d(-1)) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ~70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.
authors.affiliation: Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Kin Sing
authors.initials: KS
authors.lastname: Stephen Lee
authors.forename: Hiromi I
authors.initials: HI
authors.lastname: Wettersten
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Hu
authors.forename: Sarah
authors.initials: S
authors.lastname: Tam
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000737:chemistry*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*
chemical_list: D004852:Epoxy Compounds; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; D004851:Epoxide Hydrolases; C026219:docosapentaenoic acid
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