The utilization of curcumin as a nutraceutical in food and supplement products is often limited because of its low water solubility, poor chemical stability, and low oral bioavailability. This study examined the impact of pH, storage temperature, and molecular environment on the physical and chemical stability of pure curcumin in aqueous solutions and in oil-in-water emulsions. Unlike naturally occurring curcuminoid mixtures (that contain curcumin, demethoxy-curcumin, and bisdemethoxy-curcumin), pure curcumin was highly unstable to chemical degradation in alkaline aqueous solutions (pH ≥7.0) and tended to crystallize out of aqueous acidic solutions (pH <7). These effects were attributed to changes in the molecular structure of curcumin under different pH conditions. The curcumin crystals formed were relatively large (10-50 μm), which made them prone to rapid sedimentation. The incorporation of curcumin into oil-in-water emulsions (30% MCT, 1 mg curcumin/g MCT, d ≈ 298 nm) improved its water dispersibility and chemical stability. After incubation at 37 °C for 1 month, >85% of curcumin was retained by emulsions stored under acidic conditions (pH <7), whereas 62, 60, and 53% was retained by emulsions stored at pH 7.0, 7.4, and 8.0, respectively. There was little change in the color of curcumin-loaded emulsions when stored under acidic conditions, but their yellow color faded when stored under alkaline conditions. There was no evidence of droplet aggregation or creaming in emulsions stored for 31 days at ambient temperature. These results suggest that emulsion-based delivery systems may be suitable for improving the water dispersibility and chemical stability of curcumin, which would facilitate its application in foods and supplements.

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 VEGFand 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.

Epoxygenated fatty acids (EpFAs), which are lipid mediators produced by cytochrome P450 epoxygenases from polyunsaturated fatty acids, are important signaling molecules known to regulate various biological processes including inflammation, pain and angiogenesis. The EpFAs are further metabolized by soluble epoxide hydrolase (sEH) to form fatty acid diols which are usually less-active. Pharmacological inhibitors of sEH that stabilize endogenous EpFAs are being considered for human clinical uses. Here we review the biology of ω-3 and ω-6 EpFAs on inflammation, pain, angiogenesis and tumorigenesis.

Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/ soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.