Cannabidiol converts NF(κ)B into a tumor suppressor in glioblastoma with defined antioxidative properties


  • M.N.M. Volmar
  • J. Cheng
  • H. Alenezi
  • S. Richter
  • A. Haug
  • Z. Hassan
  • M. Goldberg
  • Y. Li
  • M. Hou
  • C. Herold-Mende
  • C.L. Maire
  • K. Lamszus
  • C. Flüh
  • J. Held-Feindt
  • G. Gargiulo
  • G.J. Topping
  • F. Schilling
  • D. Saur
  • G. Schneider
  • M. Synowitz
  • J.A. Schick
  • R.E. Kälin
  • R. Glass


  • Neuro-Oncology


  • Neuro Oncol 23 (11): 1898-1910


  • BACKGROUND: The transcription factor NF(κ)B drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NF(κ)B activity can suppress central oncogenic signalling 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(κ)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(κ)B subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which 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 predictive biomarker for CBD-sensitive tumors. CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NF(κ)B into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.