The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling.
Tamara T LahBernarda MajcMetka NovakAjda SušnikBarbara BreznikAndrej PorčnikRoman BošnjakAleksander SadikovMarta MalavoltaSelma HalilčevićJernej MlakarRoby ZomerPublished in: Cancers (2022)
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.
Keyphrases
- stem cells
- neuropathic pain
- fatty acid
- poor prognosis
- binding protein
- healthcare
- early stage
- cell therapy
- induced apoptosis
- genome wide
- spinal cord
- palliative care
- transcription factor
- gene expression
- cell proliferation
- epithelial mesenchymal transition
- quality improvement
- young adults
- resting state
- pain management
- brain injury
- endoplasmic reticulum stress
- signaling pathway
- functional connectivity
- chronic pain
- free survival
- anti inflammatory
- cancer stem cells