RT Journal Article
T1 Novel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signalling pathway
A1 García-Caballero, Melissa
A1 Blacher, S.
A1 Pauper, J.
A1 Rodríguez-Quesada, Ana María
A1 Medina-Torres, Miguel Ángel
A1 Noël, Agnès
K1 Antiangiogénicos
AB BACKGROUND AND PURPOSELymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastaticdissemination, graft rejection, lymphoedema and other inflammatory disorders. The development of new drugs that blocklymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol,a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibitlymphangiogenesis in vitro, ex vivo and in vivo.EXPERIMENTAL APPROACHWe used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in theex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and corneamodels were used. Western blotting and apoptosis analyses were carried out to search for drug targets.KEY RESULTSToluquinol inhibited LEC proliferation,migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinolinduced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reducedthe VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated thatthis drug attenuates VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependentmanner and suppresses the phosphorylationof Akt and ERK1/2.CONCLUSIONS AND IMPLICATIONSBased on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment oflymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applicationsin vascular ocular pathologies.
PB Wiley
YR 2016
FD 2016
LK http://hdl.handle.net/10630/14679
UL http://hdl.handle.net/10630/14679
LA spa
NO Br. J. Pharmacol. 173, 1966-1987, 2016
NO Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.                    This work has beensupported by personal funding by FP7-PEOPLE-2013-IEF MarieCurie Postdoctoral Fellowship (MGC). Acknowledged are thesupporting grants from the Action de Recherche Concertée(ARC) (Université de Liège), the Fonds de la RechercheScientifique-FNRS (F.R.S.-FNRS), the Foundation Against Cancer(foundation of public interest), the Centre Anticancéreux prèsl’Université de Liège, the Fonds Léon Fredericq (University ofLiège), the Interuniversity Attraction Poles Programme-BelgianScience Policy (all from Belgium) and the Plan National Cancer(« Service Public Federal » from Belgium). Research in the lab ofA.R.Q. and M.A.M. was supported by grants BIO2014-56092-R(MINECO and FEDER) and P12-CTS-1507 (AndalusianGovernment and FEDER).
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
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