anandamide and Neoplasm-Metastasis

The endocannabinoid system comprises specific cannabinoid receptors such as Cb1 and Cb2, the endogenous ligands (anandamide and 2-arachidonyl glycerol among others) and the proteins responsible for their synthesis and degradation. This system has become the focus of research in recent years because of its potential therapeutic value several disease states. The following review describes our current knowledge of the changes that occur in the endocannabinoid system during carcinogenesis and then focuses on the effects of anandamide on various aspects of the carcinogenic process such as growth, migration, and angiogenesis in tumors from various origins.

Topics: Amidohydrolases; Animals; Antineoplastic Agents; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Carcinogens; Cell Division; Cell Movement; Endocannabinoids; Enzyme Inhibitors; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Polyunsaturated Alkamides; Receptors, Cannabinoid

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.

Topics: Amides; Amidohydrolases; Antineoplastic Agents; Apoptosis; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Survival; Endocannabinoids; Epoxy Compounds; Humans; Hydrolysis; Lung; Neoplasm Metastasis; Osteosarcoma; Stereoisomerism; Wound Healing