Ethoxyfagaronine, a synthetic analogue of fagaronine that inhibits vascular endothelial growth factor-1, as a new anti-angiogeneic agent

• Published in: Investigational new drugs 2015-02, Vol.33 (1), p.75-85
• Main Authors: Ouchani, Farid, Jeanne, Albin, Thevenard, Jessica, Helesbeux, Jean-Jacques, Wahart, Amandine, Letinois, Isabelle, Duval, Olivier, Martiny, Laurent, Charpentier, Emmanuelle, Devy, Jérôme
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Aorta - drug effects; Aorta - physiology; Benzophenanthridines - pharmacology; Blood vessels; Cancer therapies; Cell adhesion & migration; Cell growth; Cell Movement - drug effects; Cell Proliferation - drug effects; Cytotoxicity; Experiments; Female; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - physiology; Humans; Investigations; Kinases; Leukemia; Life Sciences; Localization; Medical prognosis; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Oncology; Pathogenesis; Pharmaceutical sciences; Pharmacology/Toxicology; Phosphorylation; Preclinical Studies; Studies; Tumorigenesis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0184-4

Summary 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.