Cannabidiol Enhances the Inhibitory Effects of Δ⁹-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival

Abstract

The cannabinoid 1 (CB₁) and cannabinoid 2 (CB₂) receptor agonist Δ⁹-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB₁ and CB₂ receptors, can modulate the actions of Δ⁹-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ⁹-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ⁹-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ⁹-THC. In the U251 and SF126 glioblastoma cell lines, Δ⁹-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Δ⁹-THC may improve the overall effectiveness of Δ⁹-THC in the treatment of glioblastoma in cancer patients. Mol Cancer Ther; 9(1); 180–9