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.

Comparative study on alkaloids and their anti-proliferative activities from three Zanthoxylum species

“…The different fragment ions at m/z 335 and 307 could be deduced by successive neutral loss of CH 3 (15 Da) from N and CO (28 Da) from A ring of the fragment ion at m/z 350. Thus, peak 48 could be identified as fagaronine [ 25 , 29 ]. With the same fragment ions as peak 48 at m/z 350, 335, 320, 307 and 292, the parent ion ([M + H] + ) for peak 31 at m/z 512 indicated the presence of a glycoside.…”

“…With the same fragment ions as peak 48 at m/z 350, 335, 320, 307 and 292, the parent ion ([M + H] + ) for peak 31 at m/z 512 indicated the presence of a glycoside. Thus, peak 31 was identified as fagaronine-3-glucoside [ 29 ]. In the MS/MS spectrum of peak 68 , fragment ions at m/z 305 and 277 were 30 Da less than those at m/z 335 and 307 of fagaronine.…”

BBS7–SHH Signaling Activity Regulates Primary Cilia for Periodontal Homeostasis

“…These results indicate that the BBS7 may regulate the PDL cell migration through non-canonical Shh signaling. Cell migration is a critical step during angiogenesis (Ouchani et al, 2015). Angiogenesis includes destabilization of the integrated blood vessel, proliferation, migration, invasion, and tubulogenesis of endothelial cells.…”

Enrichment and analysis of quaternary alkaloids from Zanthoxylum simulans using weak cation exchange solid‐phase extraction coupled with LC–MS

“…Alkaloids, mainly found in the root or the stem bark of Z. simulans have been of immense interest due to their bioactivities, and quaternary alkaloids (QAs) as major alkaloids in this plant possess significant antitumour activities. For instance, nitidine displayed inhibitory activity on hepatic carcinoma cells by inhibiting the JAK1/STAT3 signal pathway in vitro , chelerythridine and sanguinarine showed dose‐dependent inhibitory activity by damaging the DNA of leukaemia carcinoma cells (L1210) in vitro , and fagaronine acted as angiogenesis inhibitors on leukaemia cancer cells . To explore the antitumour activities and the subsequent mechanisms of action regarding QAs from Z. simulans , one of the most important steps is to enrich and identify them from complex crude plant extracts.…”

“…For instance, nitidine displayed inhibitory activity on hepatic carcinoma cells by inhibiting the JAK1/STAT3 signal pathway in vitro, 12 chelerythridine and sanguinarine showed dose-dependent inhibitory activity by damaging the DNA of leukaemia carcinoma cells (L1210) in vitro, 13 and fagaronine acted as angiogenesis inhibitors on leukaemia cancer cells. 14 In this context, we set out to develop and optimize the method for the simultaneous enrichment and analysis of alkaloids of interest.…”