Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Guodong Zhang, Dipak Panigrahy, Lisa M. Mahakian, Jun Yang, Jun Yan Liu, Kin Sing Stephen Lee, Hiromi I. Wettersten, Arzu Ulu, Xiaowen Hu, Sarah Tam, Sung Hee Hwang, Elizabeth S. Ingham, Mark W. Kieran, Robert H Weiss, Katherine W. Ferrara, Bruce D. Hammock

Research output: Contribution to journalArticle

150 Citations (Scopus)

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 epoxyge-nases 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.

Original languageEnglish (US)
Pages (from-to)6530-6535
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number16
DOIs
StatePublished - Apr 16 2013

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Docosahexaenoic Acids
Neoplasm Metastasis
Omega-3 Fatty Acids
Growth
Acids
Neoplasms
Carcinogenesis
Omega-6 Fatty Acids
Lipids
Epoxide Hydrolases
Vascular Endothelial Growth Factor Receptor
Fish Oils
Macular Degeneration
Fibroblast Growth Factor 2
Arachidonic Acid
Cytochrome P-450 Enzyme System
Vascular Endothelial Growth Factor A
Cell Movement
Peptide Hydrolases
Endothelial Cells

ASJC Scopus subject areas

  • General

Cite this

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. / Zhang, Guodong; Panigrahy, Dipak; Mahakian, Lisa M.; Yang, Jun; Liu, Jun Yan; Lee, Kin Sing Stephen; Wettersten, Hiromi I.; Ulu, Arzu; Hu, Xiaowen; Tam, Sarah; Hwang, Sung Hee; Ingham, Elizabeth S.; Kieran, Mark W.; Weiss, Robert H; Ferrara, Katherine W.; Hammock, Bruce D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 16, 16.04.2013, p. 6530-6535.

Research output: Contribution to journalArticle

Zhang, G, Panigrahy, D, Mahakian, LM, Yang, J, Liu, JY, Lee, KSS, Wettersten, HI, Ulu, A, Hu, X, Tam, S, Hwang, SH, Ingham, ES, Kieran, MW, Weiss, RH, Ferrara, KW & Hammock, BD 2013, 'Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 16, pp. 6530-6535. https://doi.org/10.1073/pnas.1304321110
Zhang, Guodong ; Panigrahy, Dipak ; Mahakian, Lisa M. ; Yang, Jun ; Liu, Jun Yan ; Lee, Kin Sing Stephen ; Wettersten, Hiromi I. ; Ulu, Arzu ; Hu, Xiaowen ; Tam, Sarah ; Hwang, Sung Hee ; Ingham, Elizabeth S. ; Kieran, Mark W. ; Weiss, Robert H ; Ferrara, Katherine W. ; Hammock, Bruce D. / Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 16. pp. 6530-6535.
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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 epoxyge-nases 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.",
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AU - Lee, Kin Sing Stephen

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AB - 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 epoxyge-nases 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.

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