TY  - JOUR
A1  - Martens, Sofie
A1  - Jeong, Manhyung
A1  - Tonnus, Wulf
A1  - Feldmann, Friederike
A1  - Hofmans, Sam
A1  - Goossens, Vera
A1  - Takahashi, Nozomi
A1  - Bräsen, Jan Hinrich
A1  - Lee, Eun-Woo
A1  - Veken, Pieter van der
A1  - Joossens, Jurgen
A1  - Augustyns, Koen
A1  - Fulda, Simone
A1  - Linkermann, Andreas
A1  - Song, Jaewhan
A1  - Vandenabeele, Peter
T1  - Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury
T2  - Cell death & disease
N2  - 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.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46309
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-463092
SN  - 2041-4889
N1  - Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
IS  - 6, e2904
SP  - 1
EP  - 12
PB  - Nature Publishing Group
CY  - London [u. a.]
ER  -