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Targeting glioblastoma with a brain penetrant drug that impairs brain tumour stem cells via NLE1-Notch1 complex

ABSTRACT: Brain tumour stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumour hierarchy and contribute to tumour growth, therapeutic resistance, and tumour relapse. Thus, targeting of BTSCs within the bulk of tumours represents a crucial therapeutic strategy. Here, we report that Edaravone is a potent drug that impairs BTSCs and impedes glioblastoma tumorigenesis. We show that Edaravone inhibits the self-renewal and growth of BTSCs harbouring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression profiling revealed that Edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that Edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signalling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that Edaravone treatment in preclinical models delays glioblastoma tumourigenesis, sensitizes their response to IR and prolongs the lifespan of animals. Our data suggest that repurposing of Edaravone is a promising therapeutic strategy for glioblastoma patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261132 | GEO | 2024/11/19

REPOSITORIES: GEO

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