title: Dual inhibition of MAGL and type II topoisomerase by N-phenylmaleimides as a potential strategy to reduce neuroblastoma cell growth.
abstract: The endocannabinoid system is implicated in numerous physiopathological processes while more and more pieces of evidence wave the link between this complex machinery and cancer related phenomenon. In these lines, we confirmed the effects of 2-arachidonoylglycerol (2-AG), the main endocannabinoid, on neuroblastoma cells proliferation in vitro, and proved that some N-phenylmaleimide compounds that were previously shown as MAGL inhibitors can also inhibit type 2 topoisomerase. We also shed light on their antiproliferative effects on a neuroblastoma cell line. In order to establish a link between MAGL inhibition, topoisomerase inhibition and the effects on N1E-115 cells, we tested combinations of maleimides or known endocannabinoid metabolism inhibitors and 2-AG, the major MAGL substrate, on N1E-115 cells. However, none of the inhibitors tested, except the carbamate CAY10499, managed to increase 2-AG's effects. Even the MAGL reference inhibitor JZL184 failed to induce a stronger inhibition of proliferation.
authors: Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Medicinal Chemistry Research Group (CMFA), 73 avenue E. Mounier, bte B1.73.10, 1200 Bruxelles, Belgium.
authors: Nicolas
authors: N
authors: Matuszak
authors: Laurie
authors: L
authors: Hamtiaux
authors: Brigitte
authors: B
authors: Baldeyroux
authors: Giulio G
authors: GG
authors: Muccioli
authors: Jacques H
authors: JH
authors: Poupaert
authors: Amélie
authors: A
authors: Lansiaux
authors: Didier M
authors: DM
authors: Lambert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D063388:Endocannabinoids; D005047:Etoposide / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D008301:Maleimides / Q000494:pharmacology*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009447:Neuroblastoma / Q000201:enzymology*; D010069:Oxadiazoles / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; C534918:CAY 10499; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D008301:Maleimides; D010069:Oxadiazoles; D010880:Piperidines; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; C094503:glyceryl 2-arachidonate; C028525:N-phenylmaleimide; D008994:Monoacylglycerol Lipases; D004250:DNA Topoisomerases, Type II