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

The cannabinoid 1 (CB 1 ) and cannabinoid 2 (CB 2 ) receptor agonist Δ 9 -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 CB 1 and CB 2 receptors, can modulate the actions of Δ 9 -THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ 9 -THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ 9 -THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ 9 -THC. In the U251 and SF126 glioblastoma cell lines, Δ 9 -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 Δ 9 -THC may improve the overall effectiveness of Δ 9 -THC in the treatment of glioblastoma in cancer patients. Mol Cancer Ther; 9(1); 180–9