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

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

doi:10.1186/s13046-021-02031-4

Abstract

BackgroundGlioblastoma (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).MethodsIn 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.ResultsElesclomol 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.ConclusionsOur 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.

Highlights

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
glioblastoma stem-like cells (GSCs)-derived endothelial cells generate less differentiated and highly proliferating tumor xenografts Previously, we showed that GSCs cultivated under endothelial cell conditions develop morphological, phenotypical, and functional features of endothelial cells [22]
This experiment confirmed that the GSC-derived endothelial cells (GdECs) maintain their tumorigenic potential even after endothelial differentiation and that CD34 expression identifies in vivo the most aggressive tumor cells

Summary

Introduction

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 demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). GBM carries a subpopulation of tumor initiating stem-like cells (glioblastoma stem-like cells, GSCs) that has the ability to sustain malignant properties, including initiation, growth, therapy resistance, recurrence and, should represent a primary therapeutic target [2]. GBMs are characterized by increased microvascular proliferation, which is essential for tumor growth and invasion, that is mainly mediated by vascular endothelial growth factor A (VEGF-A) signaling [3, 4]. While bevacizumab initially results in a biological response, treatment does not prevent aggressive local and diffuse spread [19] and may trigger a phenotypic change in GBM, which acquires a gliomatosis-like growth pattern, the so-called infiltrative shift [20]

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