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Cannabidiol converts NF(κ)B into a tumor suppressor in glioblastoma with defined antioxidative properties

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Item Type:Article
Title:Cannabidiol converts NF(κ)B into a tumor suppressor in glioblastoma with defined antioxidative properties
Creators Name:Volmar, M.N.M. and Cheng, J. and Alenezi, H. and Richter, S. and Haug, A. and Hassan, Z. and Goldberg, M. and Li, Y. and Hou, M. and Herold-Mende, C. and Maire, C.L. and Lamszus, K. and Flüh, C. and Held-Feindt, J. and Gargiulo, G. and Topping, G.J. and Schilling, F. and Saur, D. and Schneider, G. and Synowitz, M. and Schick, J.A. and Kälin, R.E. and Glass, R.
Abstract:BACKGROUND: The transcription factor NF(κ)B drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NF(κ)B 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 NF(κ)B 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(κ)B 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 NF(κ)B into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.
Keywords:NF(κ)B (Nuclear Factor kappa-Light-Chain-Enhancer of Activated B Cells), RELA (V-Rel Avian Reticuloendotheliosisviral Oncogene Homolog A; also designated p65 or NFKB3), Stem-Like GBM Cells, GBM Therapy, Preclinical Study, Animals, Mice
Source:Neuro-Oncology
ISSN:1522-8517
Publisher:Oxford University Press
Page Range:noab095
Date:17 April 2021
Official Publication:https://doi.org/10.1093/neuonc/noab095
PubMed:View item in PubMed

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