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

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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-.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.
Keywords
ACUTE MYELOID-LEUKEMIA, NECROPTOTIC CELL-DEATH, MIXED LINEAGE KINASE, DOMAIN-LIKE PROTEIN, NF-KAPPA-B, IN-VIVO, MULTIKINASE INHIBITOR, APOPTOSIS RESISTANCE, REGULATED NECROSIS, RENAL-CANCER

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Chicago
Martens, Sofie, Manhyung Jeong, Wulf Tonnus, Friederike Feldmann, Sam Hofmans, Vera Goossens, Nozomi Takahashi, et al. 2017. “Sorafenib Tosylate Inhibits Directly Necrosome Complex Formation and Protects in Mouse Models of Inflammation and Tissue Injury.” Cell Death & Disease 8.
APA
Martens, Sofie, Jeong, M., Tonnus, W., Feldmann, F., Hofmans, S., Goossens, V., Takahashi, N., et al. (2017). Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury. CELL DEATH & DISEASE, 8.
Vancouver
1.
Martens S, Jeong M, Tonnus W, Feldmann F, Hofmans S, Goossens V, et al. Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury. CELL DEATH & DISEASE. 2017;8.
MLA
Martens, Sofie, Manhyung Jeong, Wulf Tonnus, et al. “Sorafenib Tosylate Inhibits Directly Necrosome Complex Formation and Protects in Mouse Models of Inflammation and Tissue Injury.” CELL DEATH & DISEASE 8 (2017): n. pag. Print.
@article{8528670,
  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-.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.},
  articleno    = {e2904},
  author       = {Martens, Sofie and Jeong, Manhyung and Tonnus, Wulf and Feldmann, Friederike and Hofmans, Sam and Goossens, Vera and Takahashi, Nozomi and Braesen, Jan Hinrich and Lee, Eun-Woo and Van der Veken, Pieter and Joossens, Jurgen and Augustyns, Koen and Fulda, Simone and Linkermann, Andreas and Song, Jaewhan and Vandenabeele, Peter},
  issn         = {2041-4889},
  journal      = {CELL DEATH \& DISEASE},
  language     = {eng},
  pages        = {12},
  title        = {Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury},
  url          = {http://dx.doi.org/10.1038/cddis.2017.298},
  volume       = {8},
  year         = {2017},
}

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