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- W2726753871 endingPage "e2904" @default.
- W2726753871 startingPage "e2904" @default.
- W2726753871 abstract "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- κ B 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." @default.
- W2726753871 created "2017-07-14" @default.
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- W2726753871 date "2017-06-29" @default.
- W2726753871 modified "2023-10-18" @default.
- W2726753871 title "Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury" @default.
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- W2726753871 doi "https://doi.org/10.1038/cddis.2017.298" @default.