Show simple item record Varga Attila Gyulavari Pál Greff Zoltán Futosi Krisztina Németh Tamás Simon-Szabó Laura Kerekes Krisztina Szántai-Kis Csaba Brauswetter Diána Kokas Márton Borbély Gábor Erdei Anna Mócsai Attila Kéri György Vántus Tibor 2015-06-09T07:18:00Z 2015-06-09T07:18:00Z 2015
dc.identifier.citation pagination=e0124234;journalVolume=10;journalIssueNumber=4;journalTitle=PLOS ONE; hu
dc.identifier.uri doi:10.1371/journal.pone.0124234
dc.description.abstract Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-alpha -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways. hu
dc.relation.ispartof urn:issn:1932-6203
dc.title Targeting vascular endothelial growth factor receptor 2 and protein kinase d1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro. hu
dc.type Journal Article hu 2015-05-05T08:31:43Z
dc.language.rfc3066 en hu
dc.identifier.mtmt 2889027
dc.identifier.pubmed 25874616
dc.contributor.department MTA-SE Pathobiokémiai Kutatócsoport (2006-ig: MTA-SE Peptid-Biokémiai Kutatócsoport)
dc.contributor.department SE/AOK/I/Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet
dc.contributor.department E/AOK/I/Élettani Intézet
dc.contributor.institution Semmelweis Egyetem

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