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 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.

New Avenues and Major Achievements in Phytocompounds Research for Glioblastoma Therapy

“…Not only ∆9-THC, but also CBD has been evaluated in clinical trials in the context of GBM treatment. The molecular mechanisms responsible for the anti-tumor effect exerted by CBD include, among others, targeting glioma stem cells and cancer-related signaling pathways [107,108], influencing the tumor microenvironment (TME) [109], and producing reactive oxygen species (ROS) in tumor cells [110]. Overall, numerous in vitro and in vivo studies showing beneficial effects of CBD against GBM cells (just to mention a few most recent studies [107,[109][110][111][112]) paved the way for clinical trials evaluating the impact of this cannabinoid on humans.…”

TUFM in health and disease: exploring its multifaceted roles

“…Glioblastoma is the most common malignant primary brain tumor in adults, with the worst prognosis and overall survival approximately 15 months ( 70 ). TUFM has been proposed as a potential universal biomarker for glioblastoma ( 71 – 74 ). The protein levels of TUFM are found to be higher and comparable in glioblastoma tissue, neural stem cells (NSCs), glioblastoma stem cells (GSCs), and glioblastoma cell lines U251MG and U87MG, compared with normal brain tissue.…”

SOX2 in Glioblastoma: Regulation Mechanisms and A Potential Therapeutic Target

“…In addition, PBI-05204 is a specially formulated herbal medicinal product consisting of Nerium Oleander extract modified with supercritical CO2, which has the ability to cross the blood-brain barrier and penetrate into brain tissue. The amount and size of newly formed neurospheres as well as the expression of SOX2, CXCR4 and CD44 have been shown to be significantly decreased in the presence of PBI-05204, thus reducing self-renewal and GSC stemness by negatively regulating the expression of PI3k/ Akt/ mTOR pathway (Colapietro et al, 2020) [129]. These results were consistent with another studies that shows the cytotoxic effects and anticancer therapeutic efficacy of Cannabidiol, Cannabigerol (Lah et al, 2022) [130], hydrazinobenzoylcurcumin (HBC) (Shin [132], a derivative of monoacetylated antroquinonol, which is a bioactive extract of Antrodia camphorate, on GSCs by significantly decreasing the expression of SOX2 and thus significantly inhibited their self-renewal ability.…”