1. Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties
- Author
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Joel Schick, Dieter Saur, Charlotte Flüh, Yuping Li, Franz Schilling, Sven Richter, Katrin Lamszus, Haitham Alenezi, Michael Synowitz, Marie N. M. Volmar, Günter Schneider, Janka Held-Feindt, Alisha Haug, Jiying Cheng, Mengzhuo Hou, Christel Herold-Mende, Rainer Glass, Maria Goldberg, Gaetano Gargiulo, Zonera Hassan, Geoffrey J. Topping, Cecile L. Maire, and Roland E. Kälin
- Subjects
0301 basic medicine ,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 ,Cancer Research ,Transgene ,Apoptosis ,Antioxidants ,law.invention ,03 medical and health sciences ,Transactivation ,RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A ,also designated p65 or NF-κB3) ,0302 clinical medicine ,preclinical study ,law ,Neoplasms ,Glioma ,Cell Line, Tumor ,AcademicSubjects/MED00300 ,Medicine ,Cannabidiol ,Humans ,Transcription factor ,Cannabinoids ,business.industry ,Tumor Suppressor Proteins ,stem-like GBM cells ,NF-kappa B ,Transcription Factor RelA ,Editorials ,medicine.disease ,GBM therapy ,ddc ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Tumor progression ,NF-κB (nuclear factor kappa-light-chain enhancer of activated B cells) ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,Cancer research ,Suppressor ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Signal transduction ,business ,Glioblastoma - Abstract
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.
- Published
- 2020