Bruce D. Hammock, PhD [ View bio ] and Guodong Zhang, PhD(University of California, Davis)
Lipid mediators, which are endogenous signaling molecules generated from fatty acids by the action of cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) enzymes, regulate numerous biological processes including angiogenesis and tumorigenesis. These mediators are named as part of the arachidonic acid (ARA) cascade since the ARA metabolites were the first studied. The lipid mediators from the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes are the best studied. They largely are proinflammatory, nociceptive, and hypertensive. In contrast epoxides of ARA (termed EETs) from the cytochrome P450 (CYP) branch of the cascade have the opposite effects and reduce inflammation, pain and hypertension. The EETs are largely degraded by the soluble epoxide hydrolase (sEH) and inhibitors of the sEH enzyme also reduce inflammation, blood pressure and pain in multiple species. Surprisingly the epoxydocosapentaenoic acids (EDPs), which are the CYP epoxygenase metabolites of the omega-3 docosahexaenoic acid (DHA), are even more powerful at reducing inflammatory and neuropathic pain and blood pressure than are the EETs from ARA.
The effects of the CYP-derived lipid mediators on angiogenesis and cancer are largely unknown. We earlier reported that the omega-6 EETs are mildly angiogenic when stabilized by sEH inhibitors leading to increased wound healing but a slight increase in the growth and metastasis of solid tumors. Surprisingly the epoxydocosapentaenoic acids (EDPs) derived from DHA by the CYP pathway are strongly anti-angiogenic. EDPs inhibit vascular endothelial growth factor (VEGF)- and fibroblast growth factor-2 (FGF-2)-induced angiogenesis in vivo, and EDPs but not EETs suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2 (VEGFR2)-dependent mechanism. When EDPs (0.05 mg/kg/day) are co-administered with a low-dose of a sEH inhibitor, EDPs are stabilized in circulation, causing ~70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, EETs increase primary tumor growth under these conditions. Together, these results demonstrate EETs and EDPs as novel endogenous regulators of angiogenesis and tumorigenesis, and implicate the CYP/sEH pathway as a novel therapeutic target for angiogenic diseases such as cancer. sEH inhibitors have been developed with picomolar potency and good oral PK-ADME. They are being evaluated for multiple indications including COPD and treatment of neuropathic pain. Their efficacy in reducing blood pressure, pain and inflammation appears higher when used with an omega-3 rich diet. However, the same drug has opposite effects on angiogenesis and tumor growth with an omega-3 vs omega-6 epoxide background (EDP vs EET).
The pan kinase inhibitors Sorafenib and Regorafenib are low nanomolar sEH inhibitors. It is hypothesized that their sEH inhibition reduces off target effects of these chemotherapy agents. The above data on the anti-angiogenic effects of the omega-3 EDPs suggests that a diet low in ARA and high in DHA could be used with the above kinase inhibitors to reduce off target effects and possibly increase efficacy by blocking angiogenesis while not further inhibiting VEGF receptor kinase.
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