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Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity

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,...

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Autores principales: Lecis, D, De Cesare, M, Perego, P, Conti, A, Corna, E, Drago, C, Seneci, P, Walczak, H, Colombo, M P, Delia, D, Sangaletti, S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847325/
https://www.ncbi.nlm.nih.gov/pubmed/24232096
http://dx.doi.org/10.1038/cddis.2013.449
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author Lecis, D
De Cesare, M
Perego, P
Conti, A
Corna, E
Drago, C
Seneci, P
Walczak, H
Colombo, M P
Delia, D
Sangaletti, S
author_facet Lecis, D
De Cesare, M
Perego, P
Conti, A
Corna, E
Drago, C
Seneci, P
Walczak, H
Colombo, M P
Delia, D
Sangaletti, S
author_sort Lecis, D
collection PubMed
description 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.
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spelling pubmed-38473252013-12-03 Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity Lecis, D De Cesare, M Perego, P Conti, A Corna, E Drago, C Seneci, P Walczak, H Colombo, M P Delia, D Sangaletti, S Cell Death Dis Original Article 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. Nature Publishing Group 2013-11 2013-11-14 /pmc/articles/PMC3847325/ /pubmed/24232096 http://dx.doi.org/10.1038/cddis.2013.449 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Lecis, D
De Cesare, M
Perego, P
Conti, A
Corna, E
Drago, C
Seneci, P
Walczak, H
Colombo, M P
Delia, D
Sangaletti, S
Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title_full Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title_fullStr Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title_full_unstemmed Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title_short Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
title_sort smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847325/
https://www.ncbi.nlm.nih.gov/pubmed/24232096
http://dx.doi.org/10.1038/cddis.2013.449
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