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New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53

BACKGROUND: p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-ty...

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Autores principales: Sorriento, D, Del Giudice, C, Bertamino, A, Ciccarelli, M, Gomez-Monterrey, I, Campiglia, P, Novellino, E, Illario, M, Trimarco, B, De Luca, N, Iaccarino, G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453617/
https://www.ncbi.nlm.nih.gov/pubmed/25422906
http://dx.doi.org/10.1038/bjc.2014.577
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author Sorriento, D
Del Giudice, C
Bertamino, A
Ciccarelli, M
Gomez-Monterrey, I
Campiglia, P
Novellino, E
Illario, M
Trimarco, B
De Luca, N
Iaccarino, G
author_facet Sorriento, D
Del Giudice, C
Bertamino, A
Ciccarelli, M
Gomez-Monterrey, I
Campiglia, P
Novellino, E
Illario, M
Trimarco, B
De Luca, N
Iaccarino, G
author_sort Sorriento, D
collection PubMed
description BACKGROUND: p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity. METHODS: In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot. RESULTS: Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth. CONCLUSIONS: Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity.
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spelling pubmed-44536172016-01-06 New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53 Sorriento, D Del Giudice, C Bertamino, A Ciccarelli, M Gomez-Monterrey, I Campiglia, P Novellino, E Illario, M Trimarco, B De Luca, N Iaccarino, G Br J Cancer Translational Therapeutics BACKGROUND: p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity. METHODS: In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot. RESULTS: Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth. CONCLUSIONS: Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity. Nature Publishing Group 2015-01-06 2014-11-25 /pmc/articles/PMC4453617/ /pubmed/25422906 http://dx.doi.org/10.1038/bjc.2014.577 Text en Copyright © 2015 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Translational Therapeutics
Sorriento, D
Del Giudice, C
Bertamino, A
Ciccarelli, M
Gomez-Monterrey, I
Campiglia, P
Novellino, E
Illario, M
Trimarco, B
De Luca, N
Iaccarino, G
New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title_full New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title_fullStr New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title_full_unstemmed New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title_short New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
title_sort new small molecules, isa27 and sm13, inhibit tumour growth inducing mitochondrial effects of p53
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453617/
https://www.ncbi.nlm.nih.gov/pubmed/25422906
http://dx.doi.org/10.1038/bjc.2014.577
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