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

Marie N.M. Volmar, Jiying Cheng, Haitham Alenezi, Sven Richter, Alisha Haug, Zonera Hassan, Maria Goldberg, Yuping Li, Mengzhuo Hou, Christel Herold-Mende, Cecile L. Maire, Katrin Lamszus, Charlotte Flüh, Janka Held-Feindt, Gaetano Gargiulo, Geoffrey J. Topping, Franz Schilling, DIeter Saur, Günter Schneider, Michael SynowitzJoel A. Schick, Roland E. Kälin, Rainer Glass

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)1898-1910
Number of pages13
JournalNeuro-Oncology
Volume23
Issue number11
DOIs
StatePublished - 1 Nov 2021
Externally publishedYes

Keywords

  • GBM therapy
  • NF-κB (nuclear factor kappa-light-chain enhancer of activated B cells)
  • RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A; also designated p65 or NF-κB3)
  • preclinical study
  • stem-like GBM cells

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