Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis.
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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 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.
Zhang, G., Panigrahy, D., Mahakian, L. M., Yang, J., Liu, J., Stephen Lee, K. S., ... Hammock, B. D.
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Zhang, Guodong||Panigrahy, Dipak||Mahakian, Lisa M||Yang, Jun||Liu, Jun-Yan||Stephen Lee, Kin Sing||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
