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.

中文翻译：

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Omega-3内源性大麻环氧化物的抗肿瘤发生特性。

越来越多的研究将炎症与肿瘤进展联系在一起。膳食中的ω-3脂肪酸，例如二十二碳六烯酸（DHA），已被证明可通过转化为环氧化物代谢物来抑制肿瘤的生长。或者，将DHA酶促转化为二十二碳六烯基乙醇酰胺（DHEA），这是一种具有抗增殖活性的内源性大麻素。最近，我们报道了一种新型的消炎性DHEA-环氧衍生物，称为环氧二十二碳五烯-乙醇酰胺（EDP-EA），它同时含有乙醇酰胺和环氧部分。在本文中，我们研究了骨肉瘤（OS）模型中EDP-EA的抗肿瘤发生特性。首先，我们显示与正常小鼠相比，转移性肺中EDP-EA的含量增加了约80％。我们发现，不同EDP-EA区域异构体的凋亡和抗迁移能力存在显着差异，通过大麻素受体1（CB1）部分介导。接下来，我们合成了最促凋亡的区域异构体的衍生物。这些衍生物降低了对脂肪酸酰胺水解酶（FAAH）的水解敏感性，并增加了CB1选择性结合。总的来说，我们报告了一类新的EDP-EA，它们在OS中表现出抗血管生成，抗肿瘤生成和抗迁移的特性。