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

Volmar, Marie N. M.; Cheng, Jiying; Alenezi, Haitham; Richter, Sven; Haug, Alisha; Hassan, Zonera; Goldberg, Maria; Li, Yuping; Hou, Mengzhuo; Herold-Mende, Christel; Maire, Cecile L.; Lamszus, Katrin; Flueh, Charlotte; Held-Feindt, Janka; Gargiulo, Gaetano; Topping, Geoffrey J.; Schilling, Franz; Saur, Dieter; Schneider, Gunter; Synowitz, Michael; Schick, Joel A.; Kalin, Roland E. and Glass, Rainer (2021): Cannabidiol converts NF-kappa B into a tumor suppressor in glioblastoma with defined antioxidative properties. In: Neuro-Oncology, Vol. 23, No. 11: pp. 1898-1910

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1522-8517
• Language: English