Abstract
Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM.
Highlights
Glioblastoma multiforme (GBM) is the most frequent primary tumour of the central nervous system (CNS) in adults [1]
A secondary screen conducted in both glioblastoma-initiating cells (GIC)#1 and GIC#9, from mesenchymal and classical subtypes, respectively (Table 1, Figure 1C) allowed us to exclude 33 molecules, as they exhibited no effect on GIC viability, and were considered as false positives from the primary screen
Four compounds were identified as frequent hitters that previously demonstrated toxicity in other cancer cell lines screened in our laboratory
Summary
Glioblastoma multiforme (GBM) is the most frequent primary tumour of the central nervous system (CNS) in adults [1]. Current standard treatment for GBM is palliative in nature, typically involving de-bulking surgery followed by radiotherapy and DNA-alkylating chemotherapeutic agents to eliminate the remaining cells. The recent introduction of the Stupp protocol combining radiation therapy with adjuvant chemotherapeutic agent temozolomide (TMZ) has improved GBM 5 year survival from 2% to approximately 10% [2, 3]. Prognosis for GBM patients remains extremely poor despite these advances, with median survival reported at 14.6 months [2, 4]. The poor longterm survival rates in GBM have been in part attributed to the uncontrolled recurrence of the primary disease following initial therapy
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