Please use this identifier to cite or link to this item:
Full metadata record
DC FieldValueLanguage
dc.creatorSchnekenburger M.
dc.creatorMathieu V.
dc.creatorLefranc F.
dc.creatorJang J.Y.
dc.creatorMasi M.
dc.creatorKijjoa A.
dc.creatorEvidente A.
dc.creatorKim H.-J.
dc.creatorKiss R.
dc.creatorDicato M.
dc.creatorHan B.W.
dc.creatorDiederich M.
dc.description.abstractNAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. © 2018 by the authors.
dc.description.sponsorshipAcknowledgments: M.S. was supported by a “Waxweiler grant for cancer prevention research” from the Action Lions “Vaincre le Cancer.” This work was supported by Télévie Luxembourg, the «Recherche Cancer et Sang» foundation and the «Recherches Scientifiques Luxembourg» association. The authors thank the «Een Häerz fir Kriibskrank Kanner» association and the Action Lions “Vaincre le Cancer” for generous support. M.Die. and B.W.H. are supported by the Tumor Microenvironment GCRC (2011-0030001) from the National Research Foundation funded by the Ministry of Science and ICT of Korea. R.K. is a director of research with the Fonds National de la Recherche Scientifique (FNRS; Belgium).
dc.relation.ispartofMolecules, vol. 23(2):333
dc.subjectantineoplastic agent
dc.subjecthistone deacetylase inhibitor
dc.subjectprotein binding
dc.subjectSIRT1 protein, human
dc.subjectSIRT2 protein, human
dc.subjectSIRT3 protein, human
dc.subjectsirtuin 1
dc.subjectsirtuin 2
dc.subjectsirtuin 3
dc.subjectalpha helix
dc.subjectantagonists and inhibitors
dc.subjectbeta sheet
dc.subjectbinding site
dc.subjectgene expression regulation
dc.subjectisolation and purification
dc.subjectmolecular docking
dc.subjectprotein domain
dc.subjectprotein processing
dc.subjectAntineoplastic Agents
dc.subjectBinding Sites
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectHistone Deacetylase Inhibitors
dc.subjectMolecular Docking Simulation
dc.subjectProtein Binding
dc.subjectProtein Conformation, alpha-Helical
dc.subjectProtein Conformation, beta-Strand
dc.subjectProtein Interaction Domains and Motifs
dc.subjectProtein Processing, Post-Translational
dc.subjectSirtuin 1
dc.subjectSirtuin 2
dc.subjectSirtuin 3
dc.titleThe fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition
dc.typeArtigo em Revista Científica Internacional
dc.contributor.uportoCIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental
Appears in Collections:CIIMAR - Artigo em Revista Científica Internacional

Files in This Item:
File Description SizeFormat 
Schnekenburger M_2018.pdf2.6 MBAdobe PDFThumbnail

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.