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.
Bibliographical noteFunding Information:
Acknowledgements. Research in the group of Professor P. Vandenabeele is supported by grants from the Vlaams Instituut voor Biotechnologie (VIB), from Ghent University (MRP, GROUP-ID consortium), a grant from the 'Foundation against Cancer' (2012-188 and FAF-F/2016/865), grants from the Fonds voor Wetenschap-pelijk Onderzoek Vlaanderen (FWO) (FWO G.0875.11, FWO G.0A45.12N, FWO G.0787.13N, FWO G.0E04.16N), grants from the Flemish Government (Methusalem BOF09/01M00709 and BOF16/MET_V/007), a grant from the Belgian science policy office (BELSPO)(IAP 7/32). SM was supported by the ‘Institute for the promotion of Innovation by Science and Technology in Flanders’ (IWT). We thank Stephanie Kourula and Divert Tatyana for their help with the TNF-induced SIRS model, Ria Roelandt for providing recombinant kinase material and Jolien Bridelance for providing the L929sAhFas MLKL-/-inducible mMLKL-Flag and mMLKL-S345D-Flag cells. Research in the Linkermann laboratory is supported by the German Research Foundation (DFG) in the cluster of excellence ‘Inflammation at Interfaces’, EXC306. Research in the Fulda group is supported by grants from the Deutsche Forschungsgemeinschaft, the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 675448, BMBF and IUAP VII. This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) (to J. Song).
© The Author(s) 2017.
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research