The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1
Tamara T Lah1,2, Bernarda Majc1,2, Metka Novak1
1Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia.
Abstract:
Glioblastoma (GBM) is one of the most aggressive cancers, comprising 60-70% of all gliomas. The large G-protein-coupled receptor family includes cannabinoid receptors CB1, CB2, GPR55, and non-specific ion receptor protein transporters TRPs. First, we found up-regulated CNR1, GPR55, and TRPV1 expression in glioma patient-derived tissue samples and cell lines compared with non-malignant brain samples. CNR1 and GPR55 did not correlate with glioma grade, whereas TRPV1 negatively correlated with grade and positively correlated with longer overall survival. This suggests a tumour-suppressor role of TRPV1. With respect to markers of GBM stem cells, preferred targets of therapy, TRPV1 and GPR55, but not CNR1, strongly correlated with different sets of stemness gene markers: NOTCH, OLIG2, CD9, TRIM28, and TUFM and CD15, SOX2, OCT4, and ID1, respectively. This is in line with the higher expression of TRPV1 and GPR55 genes in GSCs compared with differentiated GBM cells. Second, in a panel of patient-derived GSCs, we found that CBG and CBD exhibited the highest cytotoxicity at a molar ratio of 3:1. We suggest that this mixture should be tested in experimental animals and clinical studies, in which currently used Δ9-tetrahydrocannabinol (THC) is replaced with efficient and non-psychoactive CBG in adjuvant standard-of-care therapy.
Insights
Cannabinoid receptors (CNR1, GPR55) and TRPV1 are upregulated in glioblastoma. TRPV1 shows tumor-suppressor activity, while CBG and CBD mixtures demonstrate potent anti-glioblastoma stem cell effects.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer.
- Cannabinoid receptors (CB1, CB2), GPR55, and transient receptor potential (TRP) channels are implicated in cancer.
- Understanding their role in GBM is crucial for developing new therapies.
Purpose of the Study:
- To investigate the expression and role of cannabinoid receptors and TRPV1 in glioblastoma.
- To evaluate the anti-cancer potential of cannabinoid-derived compounds against glioblastoma stem cells.
Main Methods:
- Gene expression analysis of CNR1, GPR55, and TRPV1 in patient-derived glioma tissues and cell lines.
- Correlation analysis between gene expression, glioma grade, and patient survival.
- Assessment of cytotoxicity of cannabigerol (CBG) and cannabidiol (CBD) on glioblastoma stem cells (GSCs).
Main Results:
- CNR1, GPR55, and TRPV1 expression were upregulated in glioma samples.
- TRPV1 expression negatively correlated with glioma grade and positively with survival, suggesting a tumor-suppressor role.
- TRPV1 and GPR55 expression correlated with GBM stem cell markers.
- A CBG:CBD molar ratio of 3:1 showed the highest cytotoxicity against GSCs.
Conclusions:
- TRPV1 may act as a tumor suppressor in glioblastoma.
- CBG and CBD, particularly in a 3:1 ratio, exhibit significant anti-GSC activity.
- This CBG:CBD combination warrants further investigation as a potential non-psychoactive adjuvant therapy for glioblastoma, possibly replacing THC.
