Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties
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Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties. / Volmar, Marie N M; Cheng, Jiying; Alenezi, Haitham; Richter, Sven; Haug, Alisha; Hassan, Zonera; Goldberg, Maria; Li, Yuping; Hou, Mengzhuo; Herold-Mende, Christel; Maire, Cecile L; Lamszus, Katrin; Flüh, Charlotte; Held-Feindt, Janka; Gargiulo, Gaetano; Topping, Geoffrey J; Schilling, Franz; Saur, Dieter; Schneider, Günter; Synowitz, Michael; Schick, Joel A; Kälin, Roland E; Glass, Rainer.
In: NEURO-ONCOLOGY, Vol. 23, No. 11, 02.11.2021, p. 1898-1910.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties
AU - Volmar, Marie N M
AU - Cheng, Jiying
AU - Alenezi, Haitham
AU - Richter, Sven
AU - Haug, Alisha
AU - Hassan, Zonera
AU - Goldberg, Maria
AU - Li, Yuping
AU - Hou, Mengzhuo
AU - Herold-Mende, Christel
AU - Maire, Cecile L
AU - Lamszus, Katrin
AU - Flüh, Charlotte
AU - Held-Feindt, Janka
AU - Gargiulo, Gaetano
AU - Topping, Geoffrey J
AU - Schilling, Franz
AU - Saur, Dieter
AU - Schneider, Günter
AU - Synowitz, Michael
AU - Schick, Joel A
AU - Kälin, Roland E
AU - Glass, Rainer
N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2021/11/2
Y1 - 2021/11/2
N2 - 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.
AB - 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.
KW - Antioxidants
KW - Apoptosis
KW - Cannabidiol/pharmacology
KW - Cell Line, Tumor
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma/drug therapy
KW - Humans
KW - NF-kappa B/metabolism
KW - Transcription Factor RelA
KW - Tumor Suppressor Proteins
U2 - 10.1093/neuonc/noab095
DO - 10.1093/neuonc/noab095
M3 - SCORING: Journal article
C2 - 33864076
VL - 23
SP - 1898
EP - 1910
JO - NEURO-ONCOLOGY
JF - NEURO-ONCOLOGY
SN - 1522-8517
IS - 11
ER -