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Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties

BACKGROUND: The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this...

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Detalles Bibliográficos
Autores principales: Volmar, Marie N M, Cheng, Jiying, Alenezi, Haitham, Richter, Sven, Haug, Alisha, Hassan, Zonera, Goldberg, Maria, Li, Yuping, Hou, Mengzhuo, Herold-Mende, Christel, Maire, Cecile L, Lamszus, Katrin, Flüh, Charlotte, Held-Feindt, Janka, Gargiulo, Gaetano, Topping, Geoffrey J, Schilling, Franz, Saur, Dieter, Schneider, Günter, Synowitz, Michael, Schick, Joel A, Kälin, Roland E, Glass, Rainer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563328/
https://www.ncbi.nlm.nih.gov/pubmed/33864076
http://dx.doi.org/10.1093/neuonc/noab095
Descripción
Sumario:BACKGROUND: The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-κB can be converted into a tumor suppressor by the non-psychotropic cannabinoid cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study, we performed pharmacological assays, gene expression profiling, biochemical, and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM datasets. RESULTS: We found that CBD promotes DNA binding of the NF-κB subunit RELA and simultaneously prevents RELA phosphorylation on serine-311, a key residue that permits genetic transactivation. Strikingly, sustained DNA binding by RELA-lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen species (ROS), while high ROS content in other tumors blocked CBD-induced hGSC death. Consequently, ROS levels served as a predictive biomarker for CBD-sensitive tumors. CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NF-κB into a tumor suppressor and suggests a promising repurposing option for GBM therapy.