首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
Authors:D Lecis  M De Cesare  P Perego  A Conti  E Corna  C Drago  P Seneci  H Walczak  M P Colombo  D Delia  S Sangaletti
Institution:1.Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy;2.Institute of Biomolecular Chemistry, National Research Council, Catania 25126, Italy;3.Department of Chemistry, University of Milan, Viale Golgi 19, Milan 20133, Italy;4.CISI scrl, Via Fantoli 16/15, Milan 20138, Italy;5.Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK
Abstract:Smac mimetics (SMs) comprise a class of small molecules that target members of the inhibitor of apoptosis family of pro-survival proteins, whose expression in cancer cells hinders the action of conventional chemotherapeutics. Herein, we describe the activity of SM83, a newly synthesised dimeric SM, in two cancer ascites models: athymic nude mice injected intraperitoneally with IGROV-1 human ovarian carcinoma cells and immunocompetent BALB/c mice injected with murine Meth A sarcoma cells. SM83 rapidly killed ascitic IGROV-1 and Meth A cells in vivo (prolonging mouse survival), but was ineffective against the same cells in vitro. IGROV-1 cells in nude mice were killed within the ascites by a non-apoptotic, tumour necrosis factor (TNF)-dependent mechanism. SM83 administration triggered a rapid inflammatory event characterised by host secretion of TNF, interleukin-1β and interferon-γ. This inflammatory response was associated with the reversion of the phenotype of tumour-associated macrophages from a pro-tumoural M2- to a pro-inflammatory M1-like state. SM83 treatment was also associated with a massive recruitment of neutrophils that, however, was not essential for the antitumoural activity of this compound. In BALB/c mice bearing Meth A ascites, SM83 treatment was in some cases curative, and these mice became resistant to a second injection of cancer cells, suggesting that they had developed an adaptive immune response. Altogether, these results indicate that, in vivo, SM83 modulates the immune system within the tumour microenvironment and, through its pro-inflammatory action, leads cancer cells to die by necrosis with the release of high-mobility group box-1. In conclusion, our work provides evidence that SMs could be more therapeutically active than expected by stimulating the immune system.
Keywords:Smac mimetics  ovarian cancer ascites  IAPs  innate immunity  inflammation
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号