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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)
Verlagsversion Postprint Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Neuro-Oncology
Quellenangaben Band: 23, Heft: 11, Seiten: 1898-1910 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOXI)
Förderungen Wilhelm Sander Stiftung
DFG
Anni-Hofmann Stiftung