Journal
NEURO-ONCOLOGY
Volume 23, Issue 11, Pages 1898-1910Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/noab095
Keywords
GBM therapy; NF-kappa B (nuclear factor kappa-light-chain enhancer of activated B cells); preclinical study; RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A; also designated p65 or NF-kappa B3); stem-like GBM cells
Categories
Funding
- Anni-Hofmann Stiftung
- DFG [GL691/2, SFB824]
- Wilhelm Sander Stiftung
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The study reveals that CBD can convert NF-kappa B into a tumor suppressor, sensitizing a cohort of tumors with low levels of reactive oxygen species to CBD-induced cell death, while high ROS levels in other tumors block this effect.
Background. The transcription factor NF-kappa B drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-kappa B 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-kappa B 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-kappa B 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-kappa B into a tumor suppressor and suggests a promising repurposing option for GBM therapy.
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