title: IAP antagonization promotes inflammatory destruction of vascular endothelium.
abstract: In this study, we show for the first time that the therapeutic antagonization of inhibitor of apoptosis proteins (IAPs) inhibits B16 melanoma growth by disrupting tumor vasculature. Specifically, the treatment of mice bearing B16 melanoma with an IAP antagonist compound A (Comp A) inhibits tumor growth not by inducing direct cytotoxicity against B16 cells but rather by a hitherto unrecognized antiangiogenic activity against tumor vessels. Our detailed analysis showed that Comp A treatment induces NF-κB activity in B16 tumor cells and facilitates the production of TNF. In the presence of Comp A, endothelial cells (ECs) become highly susceptible to TNF and undergo apoptotic cell death. Accordingly, the antiangiogenic and growth-attenuating effects of Comp A treatment were completely abolished in TNF-R knockout mice. This novel targeting approach could be of clinical value in controlling pathological neoangiogenesis under inflammatory condition while sparing blood vessels under normal condition.
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Witt
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Seeger
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Coutelle
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Broxtermann
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Andree
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brinkmann
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jüngst
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Astrid C
authors.initials: AC
authors.lastname: Schauss
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schüll
authors.affiliation: Institute of Molecular Immunology, Technische Universität München, München, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wohlleber
authors.affiliation: Institute of Molecular Immunology, Technische Universität München, München, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany h.kashkar@uni-koeln.de.
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000473:pathology*; D007249:Inflammation / Q000503:physiopathology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha
keywords:       IAPs; TNF; angiogenesis; tumor
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