IAP antagonization promotes inflammatory destruction of vasculature endothelium and inhibits tumor growth

摘要: The inhibitor of apoptosis (IAP) protein family encodes a group structurally related proteins that were initially identified based on their ability to inhibit cell death. Due cytoprotective properties and elevated expression levels in many types human cancer, small molecular pharmacological inhibitors IAPs (SMAC mimetics, SM) developed the last years (Kashkar, 2010; Fulda & Vucic, 2012; Bai et al, 2014). Numerous studies have focused role SM-induced death cancer cells. Accordingly, SM compounds are currently clinical trials evaluate potential therapy so far, SM-mediated is believed directly target malignant cells (Fulda Fulda, 2014; In order study underlying mechanisms more detail vivo, we used B16 melanoma mouse model with immune competent mice. obtained results demonstrated IAP antagonization by pan-IAP antagonist inhibits tumor growth vivo not inducing direct cytotoxicity towards In fact, our work showed triggers TNF-dependent disruption vasculature microenvironment. Specifically, treatment facilitated production TNF cells, which consistent previous observations concerning cellular responses exposure (Wu 2007). Two key components stroma, infiltrating endothelial vasculature, scrutinized study. While no significant differences infiltration tumors observed, found striking reduction vascularization treated SM. lack or implanted matrigel plugs wild type but TNF-R1/2-/--mice potentiated susceptibility two independent EC cultures presence SM, as major within microenvironment. Taken together, novel anti-angiogenic activity under inflammatory conditions microenvironment. This could constitute an additional perhaps complementary improve current therapies.