Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties
Marie N.M. Volmar, Jiying Cheng, Haitham Alenezi, Sven Richter, Alisha Haug, Zonera Hassan, Maria Goldberg, Yuping Li, Mengzhuo Hou, Christel Herold‐Mende, Cécile L. Maire, Katrin Lamszus, Charlotte Flüh, Janka Held‐Feindt, Gaetano Gargiulo, Geoffrey J. Topping, Franz Schilling, Dieter Saur, Günter Schneider, Michael Synowitz, Joel Schick, Roland E. Kälin, Rainer Glaß
Abstract
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.