Isocucurbitacin B inhibits gliomas through the promotion of anoikis by targeting caveolin 1

Gliomas, known for their aggressive nature, high recurrence rates, and resistance to conventional therapies, require the development of novel treatment strategies. This study emphasizes the critical role of caveolin 1 (CAV1) in glioma progression and highlights the potent anti-glioma effects of isocucurbitacin B. The compound effectively inhibits glioma cell proliferation, invasion, migration, and epithelial-mesenchymal transition, while also inducing G2/M phase arrest and promoting apoptosis. Further analysis revealed that isocucurbitacin B promotes anoikis, a form of cell death induced by detachment, by downregulating CAV1. Notably, isocucurbitacin B directly binds to CAV1, confirmed by cellular thermal shift assays and microscale thermophoresis, positioning CAV1 as a key therapeutic target. Additionally, isocucurbitacin B activates the BKCa calcium channel, resulting in increased intracellular Ca²⁺ and reduced pH, establishing a novel connection between calcium dynamics and anoikis. Overexpression of CAV1 inhibited anoikis, blocking apoptosis and promoting migration, while decreased CAV1 expression facilitated anoikis and significantly reduced glioma cell proliferation and motility. In vivo experiments using zebrafish patient-derived xenografts and orthotopic glioblastoma models further demonstrated that isocucurbitacin B effectively suppresses tumor growth by downregulating CAV1. These findings underscore the multifaceted anti-glioma potential of isocucurbitacin B and highlight CAV1 as a crucial mediator of anoikis and a promising therapeutic target in glioma treatment.