title: Ethoxyfagaronine, a synthetic analogue of fagaronine that inhibits vascular endothelial growth factor-1, as a new anti-angiogeneic agent.
abstract: Angiogenesis plays a pivotal role in tumorigenesis and also contributes to the pathogenesis of hematologic malignancies. A number of plant compounds have shown efficacy in preclinical and clinical studies and some of them possess an anti-angiogenic activity. Our present findings report anti-angiogenic activities of ethoxyfagaronine (etxfag), a synthetic derivative of fagaronine. Once determined the non-cytotoxic concentration of etxfag, we showed that the drug inhibits VEGF-induced angiogenesis in a Matrigel™ plug assay and suppresses ex vivo sprouting from VEGF-treated aortic rings. Each feature leading to neovascularization was then investigated and results demonstrate that etxfag prevents VEGF-induced migration and tube formation in human umbilical vein endothelial cells (HUVEC). Moreover, etxfag also suppresses VEGF-induced VEGFR-2 phosphorylation and inhibits FAK phosphorylation at Y-861 as well as focal adhesion complex turnover. Beside these effects, etxfag modifies MT1-MMP localization at the endothelial cell membrane. Finally, immunoprecipitation assay revealed that etxfag decreases VEGF binding to VEGFR-2. As we previously reported that etxfag is able to prevent leukemic cell invasiveness and adhesion to fibronectin, all together our data collectively support the anti-angiogenic activities of etxfag which could represent an additional approach to current anti-cancer therapies.
authors.affiliation: CNRS UMR7369 MEDyC, Laboratoire SiRMa, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Moulin de la Housse, BP 1039, 51687, Reims cedex 2, France.
authors.forename: Farid
authors.initials: F
authors.lastname: Ouchani
authors.forename: Albin
authors.initials: A
authors.lastname: Jeanne
authors.forename: Jessica
authors.initials: J
authors.lastname: Thevenard
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Helesbeux
authors.forename: Amandine
authors.initials: A
authors.lastname: Wahart
authors.forename: Isabelle
authors.initials: I
authors.lastname: Letinois
authors.forename: Olivier
authors.initials: O
authors.lastname: Duval
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charpentier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D053119:Benzophenanthridines / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D053119:Benzophenanthridines; C568781:N-methyl-12-ethoxy-2-hydroxy-3,8,9-trimethoxybenzo(c)phenanthridinium; D042461:Vascular Endothelial Growth Factor A; C002066:fagaronine; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2