Antitumorigenic Properties of Omega-3 Endocannabinoid Epoxides

作者：Roy Jahnabi; Watson Josephine E; Hong In Sup; Fan Timothy M; Das Aditi^*

来源：Journal of Medicinal Chemistry, 2018, 61(13): 5569-5579.

DOI：10.1021/acs.jmedchem.8b00243

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 similar to 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 EDPEA 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.

• 出版日期2018-7-12