Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

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dc.contributor.authorS Martens-
dc.contributor.authorM Jeong-
dc.contributor.authorW Tonnus-
dc.contributor.authorF Feldmann-
dc.contributor.authorS Hofmans-
dc.contributor.authorV Goossens-
dc.contributor.authorN Takahashi-
dc.contributor.authorJ H Brasen-
dc.contributor.authorEun Woo Lee-
dc.contributor.authorP V Veken-
dc.contributor.authorJ Joossens-
dc.contributor.authorK Augustyns-
dc.contributor.authorS Fulda-
dc.contributor.authorA Linkermann-
dc.contributor.authorJ Song-
dc.contributor.authorP Vandenabeele-
dc.date.accessioned2017-08-29-
dc.date.available2017-08-29-
dc.date.issued2017-
dc.identifier.issn2041-4889-
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/17233-
dc.description.abstractNecroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia-reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.-
dc.publisherSpringer-Nature Pub Group-
dc.titleSorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury-
dc.title.alternativeSorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury-
dc.typeArticle-
dc.citation.titleCell Death & Disease-
dc.citation.number6-
dc.citation.endPagee2904-
dc.citation.startPagee2904-
dc.citation.volume8-
dc.contributor.affiliatedAuthorEun Woo Lee-
dc.contributor.alternativeNameMartens-
dc.contributor.alternativeName정만형-
dc.contributor.alternativeNameTonnus-
dc.contributor.alternativeNameFeldmann-
dc.contributor.alternativeNameHofmans-
dc.contributor.alternativeNameGoossens-
dc.contributor.alternativeNameTakahashi-
dc.contributor.alternativeNameBrasen-
dc.contributor.alternativeName이은우-
dc.contributor.alternativeNameVeken-
dc.contributor.alternativeNameJoossens-
dc.contributor.alternativeNameAugustyns-
dc.contributor.alternativeNameFulda-
dc.contributor.alternativeNameLinkermann-
dc.contributor.alternativeName송재환-
dc.contributor.alternativeNameVandenabeele-
dc.identifier.bibliographicCitationCell Death & Disease, vol. 8, no. 6, pp. e2904-e2904-
dc.identifier.doi10.1038/cddis.2017.298-
dc.description.journalClassY-
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
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