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• W2759045495 abstract "// Doerte Langemann 1 , Magdalena Trochimiuk 1 , Birgit Appl 1 , Patrick Hundsdoerfer 2 , Konrad Reinshagen 1 and Georg Eschenburg 1 1 Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany Correspondence to: Georg Eschenburg, email: g.eschenburg@uke.de Keywords: neuroblastoma, LCL161, vincristine, NFκB, G2 cell cycle arrest Received: June 27, 2017      Accepted: August 14, 2017      Published: September 23, 2017 ABSTRACT We demonstrated sensitization for chemotherapy by Smac mimetic (SM) LCL161, a potent antagonist of inhibitor of apoptosis proteins (IAP), in neuroblastoma (NB). Vinca alkaloids, particularly vincristine (VCR), displayed the strongest impact on inhibition of proliferation and apoptosis induction in combination with LCL161. The underlying signaling pathways remain elusive, though. LCL161 induces a quick degradation of cellular IAP 1 (cIAP-1). Combination of LCL161 with VCR had only marginal effects on X-linked IAP (XIAP) protein expression. Cell death is accompanied by activation of intrinsic (caspase-9 and MMP) and extrinsic (caspase-8) pathways of apoptosis, repression of migratory potential and cell cycle arrest in G2 phase. LCL161-induced cIAP degradation leads to activation of non-canonical and blockade of canonical NF-κB pathways but not induction of apoptosis. Surprisingly NF-κB and TNF-α signaling is negligible for VCR- and VCR/LCL161-induced apoptosis since chemical inhibition of NF-κB using BAY-7085 and PBS-1086, as well as application of TNF-α blocking antibody Humira (adalimumab) has no relevant effect on cell death. Recently formation of a TNF-α-independent complex (ripoptosome) consisting of RIP1, FADD and caspase-8 following IAP inhibition by SM has been described. However, targeting of RIP1 by Necrostatin was not sufficient to influence apoptosis induced by VCR/LCL161." @default.
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• W2759045495 date "2017-09-23" @default.
• W2759045495 modified "2023-10-01" @default.
• W2759045495 title "Sensitization of neuroblastoma for vincristine-induced apoptosis by Smac mimetic LCL161 is attended by G2 cell cycle arrest but is independent of NFκB, RIP1 and TNF-α" @default.
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• W2759045495 doi "https://doi.org/10.18632/oncotarget.21193" @default.
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