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Epoxy metabolites of docosahexaenoic acid inhibit angiogenesis and tumorigenesis (644.13)

Lipid mediators, which are signaling molecules produced from fatty acids by the actions of cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) enzymes, regulate numerous biological processes including angiogenesis and tumorigenesis. Unlike the signaling lipids derived from COX and LOX enzymes, the effects of the CYP‐derived lipid mediators on cancer are largely unknown. Here we show that epoxydocosapentaenoic acids (EDPs), which are the CYP epoxygenase metabolites of omega‐3 docosahexaenoic acid (DHA), inhibit angiogenesis, tumor growth and metastasis; while the corresponding metabolites from omega‐6 arachidonic acid (ARA), epoxyeicosatrienoic acids (EETs), increase tumor progression. EDPs inhibit vascular endothelial growth factor (VEGF)‐ and fibroblast growth factor‐2 (FGF‐2)‐induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2 (VEGFR2)‐dependent mechanism. When EDPs are co‐administered with a low‐dose soluble epoxide hydrolase (sEH) inhibitor, EDPs are stabilized in circulation and primary tumor growth and metastasis are reduced by ~70%. Contrary to the effects of EDPs, EETs increase tumor progression. Together, these results demonstrate EETs and EDPs as novel endogenous regulators of angiogenesis and tumorigenesis, and suggest the CYP/sEH pathway as a novel therapeutic target for angiogenesis and cancer.