Glioblastoma (GBM) is the most frequent malignant
tumor of the central nervous system in humans with a median survival time of less than 15 months. ∆9-Tetrahydrocannabinol (
THC) and
cannabidiol (CBD) are the best-characterized components of Cannabis sativa plants with modulating effects on
cannabinoid receptors 1 and 2 (CB1 and CB2) and on orphan receptors such as GPR18 or GPR55. Previous studies have demonstrated anti-tumorigenic effects of
THC and CBD in several
tumor entities including GBM, mostly mediated via CB1 or CB2. In this study, we investigated the non-CB1/CB2 effects of
THC on the cell cycle of GBM cells isolated from human
tumor samples. Cell cycle entry was measured after 24 h upon exposure by immunocytochemical analysis of Ki67 as proliferation marker. The Ki67-reducing effect of
THC was abolished in the presence of CBD, whereas CBD alone did not cause any changes. To identify the responsible receptor for
THC effects, we first characterized the cells regarding their expression of different
cannabinoid receptors: CB1, CB2, GPR18, and GPR55. Secondly, the receptors were pharmacologically blocked by application of their selective antagonists AM281,
AM630, O-1918, and
CID16020046 (CID), respectively. All examined cells expressed the receptors, but only in presence of the GPR55 antagonist CID was the
THC effect diminished. Stimulation with the GPR55 agonist
lysophosphatidylinositol (LPI) revealed similar effects as obtained for
THC. The LPI effects were also inhibited by CBD and CID, confirming a participation of GPR55 and suggesting its involvement in modifying the cell cycle of patient-derived GBM cells.