title: Increasing antiproliferative properties of endocannabinoids in N1E-115 neuroblastoma cells through inhibition of their metabolism.
abstract: The antitumoral properties of endocannabinoids received a particular attention these last few years. Indeed, these endogenous molecules have been reported to exert cytostatic, apoptotic and antiangiogenic effects in different tumor cell lines and tumor xenografts. Therefore, we investigated the cytotoxicity of three N-acylethanolamines--N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA)--which were all able to time- and dose-dependently reduce the viability of murine N1E-115 neuroblastoma cells. Moreover, several inhibitors of FAAH and NAAA, whose presence was confirmed by RT-PCR in the cell line, induced cell cytotoxicity and favored the decrease in cell viability caused by N-acylethanolamines. The most cytotoxic treatment was achieved by the co-incubation of AEA with the selective FAAH inhibitor URB597, which drastically reduced cell viability partly by inhibiting AEA hydrolysis and consequently increasing AEA levels. This combination of molecules synergistically decreased cell proliferation without inducing cell apoptosis or necrosis. We found that these effects are independent of cannabinoid, TRPV1, PPARα, PPARγ or GPR55 receptors activation but seem to occur through a lipid raft-dependent mechanism. These findings further highlight the interest of targeting the endocannabinoid system to treat cancer. More particularly, this emphasizes the great potential benefit of designing novel anti-cancerous therapies based on the association of endocannabinoids and inhibitors of their hydrolysis.
authors: Medicinal Chemistry, Cannabinoid and Endocannabinoid Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Laurie
authors: L
authors: Hamtiaux
authors: Laurie
authors: L
authors: Hansoulle
authors: Nicolas
authors: N
authors: Dauguet
authors: Giulio G
authors: GG
authors: Muccioli
authors: Bernard
authors: B
authors: Gallez
authors: Didier M
authors: DM
authors: Lambert
mesh_terms: D000577:Amides; D000818:Animals; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D063388:Endocannabinoids; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D008660:Metabolism / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; C022203:N-acylethanolamines; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; C033595:N-oleoylethanolamine; C005958:palmidrol; C078814:anandamide