Targeting Redox Homeostasis with Arvanil Is Preferentially Cytotoxic to Glioma Stem Cells

Glioma stem cells (GSCs) are cancer stem cells in glioblastoma (GBM) that are resistant to both radiotherapy and chemotherapy and contribute to tumor recurrence. Therefore, the development of GSC-targeted therapies is urgently needed to improve the poor prognosis of GBM patients. Given the growing interest in redox homeostasis, which is closely linked to mitochondrial metabolism supporting the unique properties of GSCs, we focused on capsaicin, a widely used exogenous calcium channel agonist, and its structural analogs as candidate compounds capable of disrupting redox homeostasis in GSCs. Based on a comprehensive evaluation of the effects of the candidate compounds, we found that the capsaicin analog arvanil selectively induced cell death in GSCs with high selectivity over differentiated GSCs at concentrations that were non-toxic to normal cells. Arvanil-induced cell death was associated with a preferential elevation in intracellular reactive oxygen species (ROS) levels in GSCs over those in differentiated GSCs and was suppressed by a Ca²⁺ chelator and a mitochondria-targeted antioxidant. These results suggest that arvanil preferentially induced GSC death in association with intracellular Ca²⁺ dysregulation and mitochondria-related oxidative stress, highlighting potential vulnerabilities in the redox homeostasis of GSCs and supporting further investigations on arvanil as a feasible therapeutic approach for GBM.