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Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells en...

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Autores principales: Buccarelli, Mariachiara, D’Alessandris, Quintino Giorgio, Matarrese, Paola, Mollinari, Cristiana, Signore, Michele, Cappannini, Andrea, Martini, Maurizio, D’Aliberti, Pierluigi, De Luca, Gabriele, Pedini, Francesca, Boe, Alessandra, Biffoni, Mauro, Pallini, Roberto, Ricci-Vitiani, Lucia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273992/
https://www.ncbi.nlm.nih.gov/pubmed/34253243
http://dx.doi.org/10.1186/s13046-021-02031-4
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author Buccarelli, Mariachiara
D’Alessandris, Quintino Giorgio
Matarrese, Paola
Mollinari, Cristiana
Signore, Michele
Cappannini, Andrea
Martini, Maurizio
D’Aliberti, Pierluigi
De Luca, Gabriele
Pedini, Francesca
Boe, Alessandra
Biffoni, Mauro
Pallini, Roberto
Ricci-Vitiani, Lucia
author_facet Buccarelli, Mariachiara
D’Alessandris, Quintino Giorgio
Matarrese, Paola
Mollinari, Cristiana
Signore, Michele
Cappannini, Andrea
Martini, Maurizio
D’Aliberti, Pierluigi
De Luca, Gabriele
Pedini, Francesca
Boe, Alessandra
Biffoni, Mauro
Pallini, Roberto
Ricci-Vitiani, Lucia
author_sort Buccarelli, Mariachiara
collection PubMed
description BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). METHODS: In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. RESULTS: Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. CONCLUSIONS: Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02031-4.
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spelling pubmed-82739922021-07-13 Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth Buccarelli, Mariachiara D’Alessandris, Quintino Giorgio Matarrese, Paola Mollinari, Cristiana Signore, Michele Cappannini, Andrea Martini, Maurizio D’Aliberti, Pierluigi De Luca, Gabriele Pedini, Francesca Boe, Alessandra Biffoni, Mauro Pallini, Roberto Ricci-Vitiani, Lucia J Exp Clin Cancer Res Research BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). METHODS: In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. RESULTS: Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. CONCLUSIONS: Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02031-4. BioMed Central 2021-07-12 /pmc/articles/PMC8273992/ /pubmed/34253243 http://dx.doi.org/10.1186/s13046-021-02031-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Buccarelli, Mariachiara
D’Alessandris, Quintino Giorgio
Matarrese, Paola
Mollinari, Cristiana
Signore, Michele
Cappannini, Andrea
Martini, Maurizio
D’Aliberti, Pierluigi
De Luca, Gabriele
Pedini, Francesca
Boe, Alessandra
Biffoni, Mauro
Pallini, Roberto
Ricci-Vitiani, Lucia
Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title_full Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title_fullStr Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title_full_unstemmed Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title_short Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
title_sort elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273992/
https://www.ncbi.nlm.nih.gov/pubmed/34253243
http://dx.doi.org/10.1186/s13046-021-02031-4
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