Antitumorigenic Properties of Omega‑3 Endocannabinoid Epoxides

Accumulating
studies have linked inflammation to tumor progression.
Dietary omega-3 fatty acids, such as docosahexaenoic acid (DHA), have
been shown to suppress tumor growth through their conversion to epoxide
metabolites. Alternatively, DHA is converted enzymatically into docosahexaenoylethanolamide
(DHEA), an endocannabinoid with antiproliferative activity. Recently,
we reported a novel class of anti-inflammatory DHEA-epoxide derivative
called epoxydocospentaenoic-ethanolamide (EDP-EA) that contain both
ethanolamide and epoxide moieties. Herein, we study the antitumorigenic
properties of EDP-EAs in an osteosarcoma (OS) model. First, we show
∼80% increase in EDP-EAs in metastatic versus normal lungs
of mice. We found significant differences in the apoptotic and antimigratory
potencies of the different EDP-EA regioisomers, which were partially
mediated through cannabinoid receptor 1 (CB1). Next, we synthesized
derivatives of the most pro-apoptotic regioisomer. These derivatives
had reduced hydrolytic susceptibility to fatty acid amide hydrolase
(FAAH) and increased CB1-selective binding. Collectively, we report
a novel class of EDP-EAs that exhibit antiangiogenic, antitumorigenic,
and antimigratory properties in OS.