IAP antagonization promotes inflammatory destruction of vascular endothelium |
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| Authors: | Axel Witt Jens M Seeger Oliver Coutelle Paola Zigrino Pia Broxtermann Maria Andree Kerstin Brinkmann Christian Jüngst Astrid C Schauss Stephan Schüll Dirk Wohlleber Percy A Knolle Martin Krönke Cornelia Mauch Hamid Kashkar |
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| Affiliation: | 1. Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany;2. Department of Dermatology, University of Cologne, Cologne, Germany;3. Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany;4. Institute of Molecular Immunology, Technische Universit?t München, München, Germany |
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| 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. |
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| Keywords: | IAPs tumor TNF angiogenesis |
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