title: The insect repellent N,N-diethyl-m-toluamide (DEET) induces angiogenesis via allosteric modulation of the M3 muscarinic receptor in endothelial cells.
abstract: The insect repellent N,N-diethyl-m-toluamide (DEET) has been reported to inhibit AChE (acetylcholinesterase) and to possess potential carcinogenic properties with excessive vascularization. In the present paper, we demonstrate that DEET specifically stimulates endothelial cells that promote angiogenesis which increases tumor growth. DEET activates cellular processes that lead to angiogenesis including proliferation, migration and adhesion. This is associated with an enhancement of NO production and VEGF expression in endothelial cells. M3 silencing or the use of a pharmacological M3 inhibitor abrogates all of these effects which reveals that DEET-induced angiogenesis is M3 sensitive. The experiments involving calcium signals in both endothelial and HEK cells overexpressing M3 receptors, as well as binding and docking studies demonstrate that DEET acts as an allosteric modulator of the M3 receptor. In addition, DEET inhibited AChE which increased acetylcholine bioavailability and binding to M3 receptors and also strengthened proangiogenic effects by an allosteric modulation.
authors.affiliation: University Bretagne Loire, Université d'Angers, UFR santé, département pharmacie, Angers, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Legeay
authors.affiliation: University Bretagne Loire, Université d'Angers, UFR santé, département pharmacie, Angers, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Clere
authors.affiliation: University Bretagne Loire, Université d'Angers, UFR santé, département pharmacie, Angers, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Hilairet
authors.affiliation: GreenPharma S.A.S. 03 allée du titane, 45100 Orléans, France.
authors.forename: Quoc-Tuan
authors.initials: QT
authors.lastname: Do
authors.affiliation: GreenPharma S.A.S. 03 allée du titane, 45100 Orléans, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.affiliation: Inserm U1045-Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Quignard
authors.affiliation: Laboratoire des Récepteurs et Canaux Ioniques Membranaires (RCIM), UPRES-EA 2647, USC INRA 1330, Angers, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Apaire-Marchais
authors.affiliation: Laboratoire des Récepteurs et Canaux Ioniques Membranaires (RCIM), UPRES-EA 2647, USC INRA 1330, Angers, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lapied
authors.affiliation: University Bretagne Loire, Université d'Angers, UFR santé, département pharmacie, Angers, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Faure
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001682:Biological Availability; D020013:Calcium Signaling / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003671:DEET / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007302:Insect Repellents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007302:Insect Repellents; D043587:Receptor, Muscarinic M3; D042461:Vascular Endothelial Growth Factor A; D003671:DEET; D000109:Acetylcholine