Abstract
Brain tumor stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumor hierarchy and contribute to tumor growth, therapeutic resistance, and tumor relapse. Thus, targeting of BTSCs within the bulk of tumors represents a crucial therapeutic strategy. Here, we report that edaravone is a potent drug that impairs BTSCs in glioblastoma. We show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression analysis 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 signaling 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 tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma.
Overview
- The study focuses on brain tumor stem cells (BTSCs) and their role in glioblastoma tumor hierarchy and growth. The hypothesis being tested is whether edaravone, a potent drug, can impair BTSCs in glioblastoma. The methodology used for the experiment includes the use of preclinical models and global gene expression analysis to investigate the effects of edaravone on BTSCs and their transcriptome. The primary objective of the study is to determine whether edaravone can delay glioblastoma tumorigenesis, sensitize their response to ionizing radiation, and prolong the lifespan of animals. The study aims to provide insights into a promising therapeutic strategy for patients with glioblastoma.
Comparative Analysis & Findings
- The study compares the effects of edaravone on BTSCs and non-oncogenic neural stem cells. The results show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. The study also reveals 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, the study discovers that edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signaling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. The key findings of the study suggest that edaravone is a potent drug that can impair BTSCs in glioblastoma and delay glioblastoma tumorigenesis, sensitize their response to IR, and prolong the lifespan of animals.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study suggests that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma. The study also identifies Notch signaling pathway as a potential therapeutic target for glioblastoma. The study's limitations include the use of preclinical models, which may not fully represent the complexity of human glioblastoma. Future research directions could include the use of human glioblastoma samples and the development of personalized therapies based on the genetic and molecular characteristics of individual patients.