CSIG-20. CANNABIDIOL CONVERTS NFKB INTO A TUMOR SUPPRESSOR IN GLIOBLASTOMA WITH DEFINED ANTIOXIDATIVE PROPERTIES

The transcription factor NFKB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFKB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFKB 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. We found that CBD promotes DNA binding of the NFKB 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 fully sufficient 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. This evidence demonstrates how a clinically approved drug can convert NFKB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy

OMRT-1. Cannabidiol converts NFKB into a tumor-suppressor in glioblastoma with defined antioxidative properties

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

The effect of new water-soluble derivatives of C60 fullerene having identical substituents and one substitution CL→ME on gene expression and the activity of transcription factors NRF2 and NFkB

С применением новых наносоединений, в частности, производных фуллерена С60, возрастает вероятность контакта с ними человека. Показано, что водорастворимые производные фуллерена могут влиять на транскрипционную активность генов в эмбриональных фибробластах легких человека (ФЛЭЧ). Активация транскрипционного фактора NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) индуцирует процессы, направленные на выживание клеток, а также развитие провоспалительного ответа. Экспрессия генов, обеспечивающих защиту от стресса на клеточном уровне, запускается фактором транскрипции, NRF2 (nuclear factor [erythroid-derived 2]-like factor 2). Взаимодействие между NFkB и NRF2 в основном носит характер антагонизма. Поиск новых соединений, избирательно активирующих транскрипционный фактор NFkB и NRF2, остаётся актуальной задачей современной медицины. With the use of new nanocompounds, in particular, derivatives of fullerene C60, the likelihood of human contact with them increases. It has been shown that water-soluble derivatives of fullerene can affect the transcriptional activity of genes in human embryonic fibroblasts of the lungs (PLEC). Activation of the transcription factor NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) induces processes aimed at cell survival, as well as the development of a pro-inflammatory response. The expression of genes that provide protection against stress at the cellular level is triggered by a transcription factor, NRF2 (nuclear factor [erythroid-derived 2] -like factor 2). The interaction between NFkB and NRF2 is mainly antagonistic. The search for new compounds that selectively activate the transcription factor NFkB and NRF2 remains an urgent task of modern medicine.