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

Abstract

Background The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB 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 NFκB 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 NFκB 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 NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…on transgenic mouse brain tumor cells showed CBD-induced lack of p65 phosphorylation in Ser-311, attenuation of NF-κB signaling and ultimately promoting cancer cell death due to CBD cytotoxicity. This study suggested antagonistic activity between Nrf2 and p65 mediated by CBD [ 130 ]. It has also been shown that an attempt to apply CBD (2.5 μM) to TNFα-treated C2C12 myoblasts did not change the level of phosphorylated p65 in Ser-536 [ 123 ].…”

Flavopiridol suppresses cell proliferation and migration and induces apoptotic cell death by inhibiting oncogenic FOXM1 signaling in IDH-wild type and -mutant GBM cells

“…Also, NF-K B is shown as molecular target in GBM, and is linked to poor prognosis. NF-K B-induced genes have been shown to be promoting cell survival and proliferation of GBM cells [44]. Therefore, we investigated the effect of avopiridol on NF-K B.…”

Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future

“…NF-κB promotes the expression of ZEB-1 in glioma, which in turn represses E-cadherin and results in anoikis resistance ( 105 ). On the other hand, inhibition of the gene transactivation function of NF-κB by cannabidiol induces cell death in GBM ( 106 ).…”