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

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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.

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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Zhang, G., Panigrahy, D., Mahakian, L. M., Yang, J., Liu, J. Y., Lee, K. S. S., Wettersten, H. I., Ulu, A., Hu, X., Tam, S., Hwang, S. H., Ingham, E. S., Kieran, M. W., Weiss, R. H., Ferrara, K. W., & Hammock, B. D. (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, 110(16), 6530-6535. https://doi.org/10.1073/pnas.1304321110