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

Cited 68 time in scopus
Metadata Downloads
Title
Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury
Author(s)
S Martens; M Jeong; W Tonnus; F Feldmann; S Hofmans; V Goossens; N Takahashi; J H Brasen; Eun Woo Lee; P V Veken; J Joossens; K Augustyns; S Fulda; A Linkermann; J Song; P Vandenabeele
Bibliographic Citation
Cell Death & Disease, vol. 8, no. 6, pp. e2904-e2904
Publication Year
2017
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.
ISSN
2041-4889
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/cddis.2017.298
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.