The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling

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 <i>CNR1, GPR55</i>, and <i>TRPV1</i> expression in glioma patient-derived tissue samples and cell lines compared with non-malignant brain samples. <i>CNR1</i> and <i>GPR55</i> did not correlate with glioma grade, whereas <i>TRPV1</i> negatively correlated with grade and positively correlated with longer overall survival. This suggests a tumour-suppressor role of <i>TRPV1</i>. With respect to markers of GBM stem cells, preferred targets of therapy, <i>TRPV1</i> and <i>GPR55</i>, but not <i>CNR1</i>, strongly correlated with different sets of stemness gene markers: <i>NOTCH, OLIG2, CD9, TRIM28</i>, and <i>TUFM</i> and <i>CD15</i>, <i>SOX2, OCT4</i>, and <i>ID1</i>, respectively. This is in line with the higher expression of <i>TRPV1</i> and <i>GPR55</i> 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.