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Journal of Experimental & Clinical Cancer Research

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01-12-2021 | Glioblastoma | Research

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

Authors: Mariachiara Buccarelli, Quintino Giorgio D’Alessandris, Paola Matarrese, Cristiana Mollinari, Michele Signore, Andrea Cappannini, Maurizio Martini, Pierluigi D’Aliberti, Gabriele De Luca, Francesca Pedini, Alessandra Boe, Mauro Biffoni, Roberto Pallini, Lucia Ricci-Vitiani

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

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.

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Title: Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth
Authors: Mariachiara Buccarelli
Quintino Giorgio D’Alessandris
Paola Matarrese
Cristiana Mollinari
Michele Signore
Andrea Cappannini
Maurizio Martini
Pierluigi D’Aliberti
Gabriele De Luca
Francesca Pedini
Alessandra Boe
Mauro Biffoni
Roberto Pallini
Lucia Ricci-Vitiani
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02031-4

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