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.
Highlights
Disturbance of this balance underlies the pathogenesis of various diseases, such as inflammatory and degenerative diseases, infectious diseases and cancer.[3]
Sorafenib was identified as an effective inhibitor of both TNF- and TNF+TAK1 inhibitor (TAK1i)-induced necroptosis (Figure 1a)
Other kinase inhibitors from the screening with similar targeting profiles as Sorafenib did not protect against necroptosis (Supplementary Tables 1–3), suggesting that necroptosis inhibition by Sorafenib is not due to inhibition of its known targets (Raf[1] kinase, VEGFR1/2/3, PDGFRb, FGFR1 receptor tyrosine kinases).[29]
Summary
Disturbance of this balance underlies the pathogenesis of various diseases, such as inflammatory and degenerative diseases, infectious diseases and cancer.[3]. Sorafenib is a multikinase inhibitor that induces apoptosis of cancer cells[23,24,25] and is clinically used to treat advanced hepatocellular carcinoma (HCC), advanced renal cell carcinoma,[26] and acute myeloid leukemia (AML).[27] Sorafenib exerts anti-tumor effects by inhibiting kinases involved in cell proliferation and survival. It inhibits tumor cell proliferation[26,28] and angiogenesis[26] through inhibition of Raf[1] kinase[29] and VEGFR1/2/3, PDGFRb, FGFR1 receptor tyrosine kinases[29] respectively. Other cellular processes that are affected by Sorafenib are Received 10.5.17; Received 23.5.17; accepted 25.5.17; Edited by G Raschellà
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