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Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties
- Source :
- Neuro Oncol, Neuro-Oncology, Neuro. Oncol. 23, 1898-1910 (2021)
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
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.
- 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
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Neuro Oncol, Neuro-Oncology, Neuro. Oncol. 23, 1898-1910 (2021)
- Accession number :
- edsair.doi.dedup.....87ec1e464e8a600a7fad6acfe03ce788