32

Selected PublicationS w-3 polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice, Wang W, Yang J, Nimiya Y, Lee KSS, Sanidad K, Qi W, Sukamtoh E, Park Y, Liu Z, Zhang G. J., Nutr. Biochem. 2017, 48, 29.

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids, Rand AA, Barnych B, Morisseau C, Cajka T, Lee KSS, Panigraphy D, Hammock BD, Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 4370.

Probing the orientation of inhibitor and epoxy-eicosatrienoic acidbinding in the active site of soluble epoxide hydrolase, Lee KS, Henriksen NM, Ng CJ, Yang J, Jia W, Morisseau C, Andaya A, Gilson MK,Hammock BD, Arch. Biochem. Biophys. 2017, 613, 1.

Soluble epoxide hydrolase inhibition and epoxyeicosatrienoic acid treatment improve vascularization of engineered skin substitutes, Supp D, Hahn J, McFarland KL, Combs KA, Lee KSS, Inceoglu B, Wan D, Boyce ST, Hammock BD, Plast. Reconstr. Surg. Glob. Open 2016, 4, e1151.

Epoxy fatty acids mediate analgesia inmu-rine diabetic neuropathy, Wagner K, Lee KS, Yang J, Hammock BD, Eur. J. Pain 2016, in press.

Molecular Mechanism of Dietary Lipids and Environmental Toxicants on Human Health

My research program focuses on inves-tigating the effect of the interaction between dietary fatty acids and envi-ronmental toxicants on human health using chemical biology methods and state-of-the-art instrumentations. More specifically, we are interested in studying the molecular mecha-nism on how dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) affects human diseases. The metabolites from ome-ga-3 and omega-6 PUFAs are important lipid signaling molecules that play an important role in inflammation, blood pressure regula-tion, wound healing, cancer, pain, etc. There-fore, understanding the signaling mechanism of these potent lipid metabolites will lead to alternate treatments for diseases. Currently, we are focused on two different directions to elucidate the mechanism on how omega-3 and omega-6 PUFA metabolites affect human physiology:

1) Identification of the receptors of polyunsaturated fatty acid (PUFA) epoxides.PUFA epoxides are potent lipid mediators with anti-inflammatory, anti-hypertensive, anti-fibrotic and analgesic properties. They also play a vital role in cancer biology. However, even after two decades of research, the signaling mechanism of PUFA epoxides remain largely unknown. To tackle this challenge, we will design analogs of PUFA epoxides. Currently, we have identified several active analogs which allows us to pursue the identification of highly specific and high affinity epoxyeicosatrienoic acid receptor(s).

AssstAnt ProfessorAnd

AssistAnt Professor of PhArmAcoLogy And toxicoLogy(b. 1980)

B.S., Chemistry 2003, Hong Kong Univ. of Science and Technology;

Ph.D., Chemistry, 2010, Michigan State Univ. ;

Post-Doctoral Scholar, 2010-14 Univ. of California at Davis;

Project Scientist 2014-2016, University of California at Davis

517-884-1813

Kin Sing Stephen Lee

2) Design and synthesis of analogs of omega-3 PUFA epoxide and inhibitor of soluble epoxide hydrolase with improved druglikeness to treat diseases.Omega-3 PUFA epoxides are transient endogenous metabolites which are metabolically unstable and rapidly degraded by an enzyme called soluble epoxide hydrolase. In addition, these fatty acid epoxide are very lipophilic with poor physical properties. Therefore, they are poor drug candidates. Recently, our laboratory have employed a high-throughput screening in order to study the structure-activity-relationship of the omega-3 PUFA epoxides on fibrosis. By understanding the SAR of PUFA epoxides on fibrosis, we will be able to design analogs with better drug-like properties.

Because the soluble epoxide hydrolase (sEH) is the major metabolic enzyme for PUFA epoxides, inhibition of sEH is beneficial to human health through stabilization of PUFA epoxides in vivo. Thus, sEH becomes a prominent therapeutic target. Recently, it has been shown that sEH inhibitors are efficacious on diabetic neuropathic pain model in mice. Unfortunately, the properties of the current sEH inhibitors are not fully optimized. Therefore, we will redesign the structure of the sEH inhibitors to improve their drug-like properties particularly, the drug-target residence time because the drug-target residence time has been demonstrated to be an important drug parameter to predict in vivo efficacy of the drug.

consistent with previous reports (26, 28). Together, these resultsdesignate EDPs and EETs as unique mediators of an angiogenicswitch to regulate tumorigenesis.Previous research of omega-3 lipid signaling has mainly fo-

cused on the COX and LOX pathways (10–13), whereas theCYP pathway, which is the third branch of the lipid metaboliccascade (14–16), has received little attention (40). The presentstudy implies that the previously unappreciated CYP epoxygenasepathway could play a critical role in mediating the opposite effectsof omega-3 and omega-6 polyunsaturated fatty acids on angio-genesis and cancer. Omega-3 fatty acids have been shown to bepoor substrates of COX and LOX enzymes (17), whereas theyare highly efficient alternative substrates for numerous isoformsof CYP epoxygenases (16). Supplementation of DHA in vivoreduces the levels of EETs and increases the levels of EDPs inmost organs (16). Thus, an exchange of proangiogenic EETs withantiangiogenic and anticancer EDPs could explain the anti-angiogenic and anticancer effects of DHA. Increased formationof EDPs has also been observed in humans upon DHA supple-mentation (19, 20), suggesting our findings may also be correlatedwith the effects of DHA in humans.EETs and EDPs are best described as regulators of inflam-

mation and vascular tone (21–24). Compared with EETs, EDPsare more potent than the EETs for vasodilation (∼1,000 timesmore potent than EETs) (24) and anti-inflammation (22). Theseresults further argue that a replacement of EETs with EDPs uponomega-3 supplementation causes multiple beneficial effects. Pre-vious studies showed that EETs stimulate angiogenesis via up-regulation of VEGF (VEGF-A) in vitro and in vivo (25, 28). Herewe found that EDP had no effect on VEGF-A expression, whereasit potently inhibited the expression of VEGF-C in vitro (Fig. 1G

and Table S1). VEGF-C is a critical mediator of lymphangio-genesis (41) and is an important therapeutic target for cancer.Currently an anti–VEGF-C monoclonal antibody VGX-100 isin phase I cancer clinical trials. Further studies are needed totest whether EDP suppresses VEGF-C and the resulting lym-phangiogenesis in vivo. In addition, we demonstrate VEGFR2 asa potential cellular target for the antiangiogenic effect of EDPs.A 10-min treatment of 1 μM 19,20-EDP dramatically inhibitedVEGF-induced VEGFR2 phosphorylation in endothelial cells(Fig. 1F), supporting 19,20-EDP inhibition of angiogenesis via aVEGFR2-dependent mechanism. This is consistent with our find-ings that 19,20-EDP inhibited VEGF-induced angiogenesis in vitroand in vivo (Fig. 1). VEGFR2 is the most important VEGF re-ceptor, mediating almost all known cellular responses of VEGFand is the therapeutic target of numerous angiogenesis inhibitorson the market (30). However, a common side effect of angio-genesis inhibitors that target the VEGF–VEGFR2 pathway isthe induction of hypertension (42). Due to the extremely potentvasodilatory effects of EDPs (24), EDPs may have unique ad-vantages in antiangiogenic cancer therapy by avoiding hyperten-sion, which is a side effect associated with all current antiangiogenicdrugs. Further studies are needed to investigate the effects ofEDPs on blood pressure and other cardiovascular functions.The tissue levels of endogenous EETs and EDPs are deter-

mined by the ARA and DHA released from membrane phos-pholipids, CYP epoxygenases, and sEH. Among the most abundantepoxy lipid mediators in omega-6 fatty acid-rich and omega-3–richtissues are EETs and EDPs, respectively, which are further in-creased by genetic deletion or pharmacological inhibition of sEH(16, 43). For example, in zebrafish, 19,20-EDP was reported tobe the most abundant epoxy lipid mediator; the other epoxy

Control

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16,17-EDP

+ t-AUCB

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+ t-AUCB

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Fig. 3. EDPs inhibit tumor metastasis. (A) Lewis lung carcinoma (LLC) metastasis model in C57BL/6 mice. (B) Spontaneous LLC metastasis was decreased inEDP- and t-AUCB–treated mice relative to vehicle treatment 17 d after primary tumor removal (LLC resection). Images show representative lung metastasis intreated and control mice. (Scale bar, 1 cm.) n = 4–5 mice per group. Results are presented as means ± SEM. *P < 0.05; #P < 0.001.

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consistent with previous reports (26, 28). Together, these resultsdesignate EDPs and EETs as unique mediators of an angiogenicswitch to regulate tumorigenesis.Previous research of omega-3 lipid signaling has mainly fo-

cused on the COX and LOX pathways (10–13), whereas theCYP pathway, which is the third branch of the lipid metaboliccascade (14–16), has received little attention (40). The presentstudy implies that the previously unappreciated CYP epoxygenasepathway could play a critical role in mediating the opposite effectsof omega-3 and omega-6 polyunsaturated fatty acids on angio-genesis and cancer. Omega-3 fatty acids have been shown to bepoor substrates of COX and LOX enzymes (17), whereas theyare highly efficient alternative substrates for numerous isoformsof CYP epoxygenases (16). Supplementation of DHA in vivoreduces the levels of EETs and increases the levels of EDPs inmost organs (16). Thus, an exchange of proangiogenic EETs withantiangiogenic and anticancer EDPs could explain the anti-angiogenic and anticancer effects of DHA. Increased formationof EDPs has also been observed in humans upon DHA supple-mentation (19, 20), suggesting our findings may also be correlatedwith the effects of DHA in humans.EETs and EDPs are best described as regulators of inflam-

mation and vascular tone (21–24). Compared with EETs, EDPsare more potent than the EETs for vasodilation (∼1,000 timesmore potent than EETs) (24) and anti-inflammation (22). Theseresults further argue that a replacement of EETs with EDPs uponomega-3 supplementation causes multiple beneficial effects. Pre-vious studies showed that EETs stimulate angiogenesis via up-regulation of VEGF (VEGF-A) in vitro and in vivo (25, 28). Herewe found that EDP had no effect on VEGF-A expression, whereasit potently inhibited the expression of VEGF-C in vitro (Fig. 1G

and Table S1). VEGF-C is a critical mediator of lymphangio-genesis (41) and is an important therapeutic target for cancer.Currently an anti–VEGF-C monoclonal antibody VGX-100 isin phase I cancer clinical trials. Further studies are needed totest whether EDP suppresses VEGF-C and the resulting lym-phangiogenesis in vivo. In addition, we demonstrate VEGFR2 asa potential cellular target for the antiangiogenic effect of EDPs.A 10-min treatment of 1 μM 19,20-EDP dramatically inhibitedVEGF-induced VEGFR2 phosphorylation in endothelial cells(Fig. 1F), supporting 19,20-EDP inhibition of angiogenesis via aVEGFR2-dependent mechanism. This is consistent with our find-ings that 19,20-EDP inhibited VEGF-induced angiogenesis in vitroand in vivo (Fig. 1). VEGFR2 is the most important VEGF re-ceptor, mediating almost all known cellular responses of VEGFand is the therapeutic target of numerous angiogenesis inhibitorson the market (30). However, a common side effect of angio-genesis inhibitors that target the VEGF–VEGFR2 pathway isthe induction of hypertension (42). Due to the extremely potentvasodilatory effects of EDPs (24), EDPs may have unique ad-vantages in antiangiogenic cancer therapy by avoiding hyperten-sion, which is a side effect associated with all current antiangiogenicdrugs. Further studies are needed to investigate the effects ofEDPs on blood pressure and other cardiovascular functions.The tissue levels of endogenous EETs and EDPs are deter-

mined by the ARA and DHA released from membrane phos-pholipids, CYP epoxygenases, and sEH. Among the most abundantepoxy lipid mediators in omega-6 fatty acid-rich and omega-3–richtissues are EETs and EDPs, respectively, which are further in-creased by genetic deletion or pharmacological inhibition of sEH(16, 43). For example, in zebrafish, 19,20-EDP was reported tobe the most abundant epoxy lipid mediator; the other epoxy

Control

t-AUCB

16,17-EDP

19,20-EDP

16,17-EDP

+ t-AUCB

19,20-EDP

+ t-AUCB

Lung

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ght (

mg)

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Fig. 3. EDPs inhibit tumor metastasis. (A) Lewis lung carcinoma (LLC) metastasis model in C57BL/6 mice. (B) Spontaneous LLC metastasis was decreased inEDP- and t-AUCB–treated mice relative to vehicle treatment 17 d after primary tumor removal (LLC resection). Images show representative lung metastasis intreated and control mice. (Scale bar, 1 cm.) n = 4–5 mice per group. Results are presented as means ± SEM. *P < 0.05; #P < 0.001.

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consistent with previous reports (26, 28). Together, these resultsdesignate EDPs and EETs as unique mediators of an angiogenicswitch to regulate tumorigenesis.Previous research of omega-3 lipid signaling has mainly fo-

cused on the COX and LOX pathways (10–13), whereas theCYP pathway, which is the third branch of the lipid metaboliccascade (14–16), has received little attention (40). The presentstudy implies that the previously unappreciated CYP epoxygenasepathway could play a critical role in mediating the opposite effectsof omega-3 and omega-6 polyunsaturated fatty acids on angio-genesis and cancer. Omega-3 fatty acids have been shown to bepoor substrates of COX and LOX enzymes (17), whereas theyare highly efficient alternative substrates for numerous isoformsof CYP epoxygenases (16). Supplementation of DHA in vivoreduces the levels of EETs and increases the levels of EDPs inmost organs (16). Thus, an exchange of proangiogenic EETs withantiangiogenic and anticancer EDPs could explain the anti-angiogenic and anticancer effects of DHA. Increased formationof EDPs has also been observed in humans upon DHA supple-mentation (19, 20), suggesting our findings may also be correlatedwith the effects of DHA in humans.EETs and EDPs are best described as regulators of inflam-

mation and vascular tone (21–24). Compared with EETs, EDPsare more potent than the EETs for vasodilation (∼1,000 timesmore potent than EETs) (24) and anti-inflammation (22). Theseresults further argue that a replacement of EETs with EDPs uponomega-3 supplementation causes multiple beneficial effects. Pre-vious studies showed that EETs stimulate angiogenesis via up-regulation of VEGF (VEGF-A) in vitro and in vivo (25, 28). Herewe found that EDP had no effect on VEGF-A expression, whereasit potently inhibited the expression of VEGF-C in vitro (Fig. 1G

and Table S1). VEGF-C is a critical mediator of lymphangio-genesis (41) and is an important therapeutic target for cancer.Currently an anti–VEGF-C monoclonal antibody VGX-100 isin phase I cancer clinical trials. Further studies are needed totest whether EDP suppresses VEGF-C and the resulting lym-phangiogenesis in vivo. In addition, we demonstrate VEGFR2 asa potential cellular target for the antiangiogenic effect of EDPs.A 10-min treatment of 1 μM 19,20-EDP dramatically inhibitedVEGF-induced VEGFR2 phosphorylation in endothelial cells(Fig. 1F), supporting 19,20-EDP inhibition of angiogenesis via aVEGFR2-dependent mechanism. This is consistent with our find-ings that 19,20-EDP inhibited VEGF-induced angiogenesis in vitroand in vivo (Fig. 1). VEGFR2 is the most important VEGF re-ceptor, mediating almost all known cellular responses of VEGFand is the therapeutic target of numerous angiogenesis inhibitorson the market (30). However, a common side effect of angio-genesis inhibitors that target the VEGF–VEGFR2 pathway isthe induction of hypertension (42). Due to the extremely potentvasodilatory effects of EDPs (24), EDPs may have unique ad-vantages in antiangiogenic cancer therapy by avoiding hyperten-sion, which is a side effect associated with all current antiangiogenicdrugs. Further studies are needed to investigate the effects ofEDPs on blood pressure and other cardiovascular functions.The tissue levels of endogenous EETs and EDPs are deter-

mined by the ARA and DHA released from membrane phos-pholipids, CYP epoxygenases, and sEH. Among the most abundantepoxy lipid mediators in omega-6 fatty acid-rich and omega-3–richtissues are EETs and EDPs, respectively, which are further in-creased by genetic deletion or pharmacological inhibition of sEH(16, 43). For example, in zebrafish, 19,20-EDP was reported tobe the most abundant epoxy lipid mediator; the other epoxy

Control

t-AUCB

16,17-EDP

19,20-EDP

16,17-EDP

+ t-AUCB

19,20-EDP

+ t-AUCB

Lung

Wei

ght (

mg)

0200400600800

100012001400

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Fig. 3. EDPs inhibit tumor metastasis. (A) Lewis lung carcinoma (LLC) metastasis model in C57BL/6 mice. (B) Spontaneous LLC metastasis was decreased inEDP- and t-AUCB–treated mice relative to vehicle treatment 17 d after primary tumor removal (LLC resection). Images show representative lung metastasis intreated and control mice. (Scale bar, 1 cm.) n = 4–5 mice per group. Results are presented as means ± SEM. *P < 0.05; #P < 0.001.

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consistent with previous reports (26, 28). Together, these resultsdesignate EDPs and EETs as unique mediators of an angiogenicswitch to regulate tumorigenesis.Previous research of omega-3 lipid signaling has mainly fo-

cused on the COX and LOX pathways (10–13), whereas theCYP pathway, which is the third branch of the lipid metaboliccascade (14–16), has received little attention (40). The presentstudy implies that the previously unappreciated CYP epoxygenasepathway could play a critical role in mediating the opposite effectsof omega-3 and omega-6 polyunsaturated fatty acids on angio-genesis and cancer. Omega-3 fatty acids have been shown to bepoor substrates of COX and LOX enzymes (17), whereas theyare highly efficient alternative substrates for numerous isoformsof CYP epoxygenases (16). Supplementation of DHA in vivoreduces the levels of EETs and increases the levels of EDPs inmost organs (16). Thus, an exchange of proangiogenic EETs withantiangiogenic and anticancer EDPs could explain the anti-angiogenic and anticancer effects of DHA. Increased formationof EDPs has also been observed in humans upon DHA supple-mentation (19, 20), suggesting our findings may also be correlatedwith the effects of DHA in humans.EETs and EDPs are best described as regulators of inflam-

mation and vascular tone (21–24). Compared with EETs, EDPsare more potent than the EETs for vasodilation (∼1,000 timesmore potent than EETs) (24) and anti-inflammation (22). Theseresults further argue that a replacement of EETs with EDPs uponomega-3 supplementation causes multiple beneficial effects. Pre-vious studies showed that EETs stimulate angiogenesis via up-regulation of VEGF (VEGF-A) in vitro and in vivo (25, 28). Herewe found that EDP had no effect on VEGF-A expression, whereasit potently inhibited the expression of VEGF-C in vitro (Fig. 1G

and Table S1). VEGF-C is a critical mediator of lymphangio-genesis (41) and is an important therapeutic target for cancer.Currently an anti–VEGF-C monoclonal antibody VGX-100 isin phase I cancer clinical trials. Further studies are needed totest whether EDP suppresses VEGF-C and the resulting lym-phangiogenesis in vivo. In addition, we demonstrate VEGFR2 asa potential cellular target for the antiangiogenic effect of EDPs.A 10-min treatment of 1 μM 19,20-EDP dramatically inhibitedVEGF-induced VEGFR2 phosphorylation in endothelial cells(Fig. 1F), supporting 19,20-EDP inhibition of angiogenesis via aVEGFR2-dependent mechanism. This is consistent with our find-ings that 19,20-EDP inhibited VEGF-induced angiogenesis in vitroand in vivo (Fig. 1). VEGFR2 is the most important VEGF re-ceptor, mediating almost all known cellular responses of VEGFand is the therapeutic target of numerous angiogenesis inhibitorson the market (30). However, a common side effect of angio-genesis inhibitors that target the VEGF–VEGFR2 pathway isthe induction of hypertension (42). Due to the extremely potentvasodilatory effects of EDPs (24), EDPs may have unique ad-vantages in antiangiogenic cancer therapy by avoiding hyperten-sion, which is a side effect associated with all current antiangiogenicdrugs. Further studies are needed to investigate the effects ofEDPs on blood pressure and other cardiovascular functions.The tissue levels of endogenous EETs and EDPs are deter-

mined by the ARA and DHA released from membrane phos-pholipids, CYP epoxygenases, and sEH. Among the most abundantepoxy lipid mediators in omega-6 fatty acid-rich and omega-3–richtissues are EETs and EDPs, respectively, which are further in-creased by genetic deletion or pharmacological inhibition of sEH(16, 43). For example, in zebrafish, 19,20-EDP was reported tobe the most abundant epoxy lipid mediator; the other epoxy

Control

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16,17-EDP

+ t-AUCB

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+ t-AUCB

Lung

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Fig. 3. EDPs inhibit tumor metastasis. (A) Lewis lung carcinoma (LLC) metastasis model in C57BL/6 mice. (B) Spontaneous LLC metastasis was decreased inEDP- and t-AUCB–treated mice relative to vehicle treatment 17 d after primary tumor removal (LLC resection). Images show representative lung metastasis intreated and control mice. (Scale bar, 1 cm.) n = 4–5 mice per group. Results are presented as means ± SEM. *P < 0.05; #P < 0.001.

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Control

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19,20-EDP + sEHI

consistent with previous reports (26, 28). Together, these resultsdesignate EDPs and EETs as unique mediators of an angiogenicswitch to regulate tumorigenesis.Previous research of omega-3 lipid signaling has mainly fo-

cused on the COX and LOX pathways (10–13), whereas theCYP pathway, which is the third branch of the lipid metaboliccascade (14–16), has received little attention (40). The presentstudy implies that the previously unappreciated CYP epoxygenasepathway could play a critical role in mediating the opposite effectsof omega-3 and omega-6 polyunsaturated fatty acids on angio-genesis and cancer. Omega-3 fatty acids have been shown to bepoor substrates of COX and LOX enzymes (17), whereas theyare highly efficient alternative substrates for numerous isoformsof CYP epoxygenases (16). Supplementation of DHA in vivoreduces the levels of EETs and increases the levels of EDPs inmost organs (16). Thus, an exchange of proangiogenic EETs withantiangiogenic and anticancer EDPs could explain the anti-angiogenic and anticancer effects of DHA. Increased formationof EDPs has also been observed in humans upon DHA supple-mentation (19, 20), suggesting our findings may also be correlatedwith the effects of DHA in humans.EETs and EDPs are best described as regulators of inflam-

mation and vascular tone (21–24). Compared with EETs, EDPsare more potent than the EETs for vasodilation (∼1,000 timesmore potent than EETs) (24) and anti-inflammation (22). Theseresults further argue that a replacement of EETs with EDPs uponomega-3 supplementation causes multiple beneficial effects. Pre-vious studies showed that EETs stimulate angiogenesis via up-regulation of VEGF (VEGF-A) in vitro and in vivo (25, 28). Herewe found that EDP had no effect on VEGF-A expression, whereasit potently inhibited the expression of VEGF-C in vitro (Fig. 1G

and Table S1). VEGF-C is a critical mediator of lymphangio-genesis (41) and is an important therapeutic target for cancer.Currently an anti–VEGF-C monoclonal antibody VGX-100 isin phase I cancer clinical trials. Further studies are needed totest whether EDP suppresses VEGF-C and the resulting lym-phangiogenesis in vivo. In addition, we demonstrate VEGFR2 asa potential cellular target for the antiangiogenic effect of EDPs.A 10-min treatment of 1 μM 19,20-EDP dramatically inhibitedVEGF-induced VEGFR2 phosphorylation in endothelial cells(Fig. 1F), supporting 19,20-EDP inhibition of angiogenesis via aVEGFR2-dependent mechanism. This is consistent with our find-ings that 19,20-EDP inhibited VEGF-induced angiogenesis in vitroand in vivo (Fig. 1). VEGFR2 is the most important VEGF re-ceptor, mediating almost all known cellular responses of VEGFand is the therapeutic target of numerous angiogenesis inhibitorson the market (30). However, a common side effect of angio-genesis inhibitors that target the VEGF–VEGFR2 pathway isthe induction of hypertension (42). Due to the extremely potentvasodilatory effects of EDPs (24), EDPs may have unique ad-vantages in antiangiogenic cancer therapy by avoiding hyperten-sion, which is a side effect associated with all current antiangiogenicdrugs. Further studies are needed to investigate the effects ofEDPs on blood pressure and other cardiovascular functions.The tissue levels of endogenous EETs and EDPs are deter-

mined by the ARA and DHA released from membrane phos-pholipids, CYP epoxygenases, and sEH. Among the most abundantepoxy lipid mediators in omega-6 fatty acid-rich and omega-3–richtissues are EETs and EDPs, respectively, which are further in-creased by genetic deletion or pharmacological inhibition of sEH(16, 43). For example, in zebrafish, 19,20-EDP was reported tobe the most abundant epoxy lipid mediator; the other epoxy

Control

t-AUCB

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19,20-EDP

16,17-EDP

+ t-AUCB

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+ t-AUCB

Lung

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Fig. 3. EDPs inhibit tumor metastasis. (A) Lewis lung carcinoma (LLC) metastasis model in C57BL/6 mice. (B) Spontaneous LLC metastasis was decreased inEDP- and t-AUCB–treated mice relative to vehicle treatment 17 d after primary tumor removal (LLC resection). Images show representative lung metastasis intreated and control mice. (Scale bar, 1 cm.) n = 4–5 mice per group. Results are presented as means ± SEM. *P < 0.05; #P < 0.001.

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CYP450sO HO OH

CO2H CO2H CO2H

DHA(2C, 2J)

19,20-EDP

sEH

19,20-DiHDPAsEHIAnti-angiogenic