OMRT-1. Cannabidiol converts NFKB into a tumor-suppressor in glioblastoma with defined antioxidative properties

Abstract Background The transcription factor NFKB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFKB-activity can suppress central oncogenic signalling 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 NFKB 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 NFKB-subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which 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 predictive biomarker for CBD-sensitive tumors. Conclusions This evidence demonstrates how a clinically approved drug can convert NFKB into a tumor-suppressor and suggests a promising repurposing option for GBM-therapy.