TY - JOUR
T1 - Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
AU - Zhang, Guodong
AU - Panigrahy, Dipak
AU - Mahakian, Lisa M.
AU - Yang, Jun
AU - Liu, Jun Yan
AU - Lee, Kin Sing Stephen
AU - Wettersten, Hiromi I.
AU - Ulu, Arzu
AU - Hu, Xiaowen
AU - Tam, Sarah
AU - Hwang, Sung Hee
AU - Ingham, Elizabeth S.
AU - Kieran, Mark W.
AU - Weiss, Robert H
AU - Ferrara, Katherine W.
AU - Hammock, Bruce D.
PY - 2013/4/16
Y1 - 2013/4/16
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84876218926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876218926&partnerID=8YFLogxK
U2 - 10.1073/pnas.1304321110
DO - 10.1073/pnas.1304321110
M3 - Article
C2 - 23553837
AN - SCOPUS:84876218926
VL - 110
SP - 6530
EP - 6535
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 16
ER -