Journal Article

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

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

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Angiogenesis / Animals / Antigens / Apoptosis / Biomedical and Life Sciences / Biomedicine / Brain cancer / Brain Neoplasms - drug therapy / Brain tumors / Cancer / Cancer Research / Cancer stem cells / Cancer therapies / Cell death / Cell Line, Tumor / Cell Proliferation / Cell Survival - drug effects / Cytotoxicity / Development and progression / Elesclomol / Endothelium / Experiments / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma multiforme / Health aspects / Humans / Hydrazines - pharmacology / Hydrazines - therapeutic use / Immunology / Male / Medical equipment and supplies industry / Medical test kit industry / Mice / Mice, Inbred NOD / Monoclonal antibodies / Neovascularization / Oncology / Oxidative Stress / Prognosis / Proteins / Reactive Oxygen Species / Stem cells / Vascular endothelial growth factor