Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties

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 -