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Volmar, M.N.M.* ; Cheng, J.* ; Alenezi, H.* ; Richter, S.* ; Haug, A.* ; Hassan, Z.* ; Goldberg, M.* ; Li, Y.* ; Hou, M.* ; Herold-Mende, C.* ; Maire, C.L.* ; Lamszus, K.* ; Flüh, C.* ; Held-Feindt, J.* ; Gargiulo, G.* ; Topping, G.J.* ; Schilling, F.* ; Saur, D.* ; Schneider, G.* ; Synowitz, M.* ; Schick, J. ; Kälin, R.E.* ; Glass, R.*

Cannabidiol converts NFκB into a tumor suppressor in glioblastoma with defined antioxidative properties.

Neuro. Oncol. 23, 1898-1910 (2021)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB 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 NFκB 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 NFκB 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 NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gbm Therapy ; Nfb (nuclear Factor Kappa-light-chain-enhancer Of Activated B Cells) ; Rela (v-rel Avian Reticuloendotheliosis Viral Oncogene Homolog A ; Also Designated P65 Or Nfkb3) ; Preclinical Study ; Stem-like Gbm Cells; Neural Precursor Cells; Initiating Cells; Zeta-pkc; Metabolism; Mitochondria; Cancer
ISSN (print) / ISBN 1522-8517
e-ISSN 1523-5866
Journal Neuro-Oncology
Quellenangaben Volume: 23, Issue: 11, Pages: 1898-1910 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
Grants Wilhelm Sander Stiftung
DFG
Anni-Hofmann Stiftung