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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-06-29

AUTHORS

Sofie Martens, Manhyung Jeong, Wulf Tonnus, Friederike Feldmann, Sam Hofmans, Vera Goossens, Nozomi Takahashi, Jan Hinrich Bräsen, Eun-Woo Lee, Pieter Van der Veken, Jurgen Joossens, Koen Augustyns, Simone Fulda, Andreas Linkermann, Jaewhan Song, Peter Vandenabeele

ABSTRACT

Necroptosis 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. More... »

PAGES

e2904

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/cddis.2017.298

    DOI

    http://dx.doi.org/10.1038/cddis.2017.298

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1090287504

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28661484


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