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

Abstract

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.

A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

“…Recent results by McAllister's group indicate that CBD, which had been previously shown to reduce the growth of different types of tumor xenografts by itself (21)(22)(23)25), enhance the inhibitory effects of THC on the viability of glioma cells (26). In line with this idea, in this report we find that the combination of submaximal doses of THC and CBD reduce tumor growth with a similar potency compared with an effective dose of THC.…”

“…22), a mechanism that seems to operate also in glioma cells (23,25). Of note, the combined administration of THC and CBD is being therapeutically explored (10,20,26), although its effects on the proliferation and survival of cancer cells have only been analyzed in vitro (26).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…CBD inhibits cancer growth and induces apoptosis by generating ROS and upregulating caspase proteases by inducing endoplasmic reticulum and mitochondrial stress, whereas ⌬ 9 -THC inhibition of cancer is CB1 and CB2 receptor-mediated and leads to the activation of MAPK/ERK pathways and ceramide accumulation. Thus, combining these mechanisms by using together CBD and ⌬ 9 -THC is likely to produce synergistic effects in several diseases (527). Indeed, in an animal model of MS spasticity, the indication for which Sativex is approved in more than 26 countries, this botanical drug is more efficacious at reducing limb spasticity than ⌬ 9 -THC alone, even though CBD is inactive in this test (356).…”

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

“…It has been shown that cannabidiol (CBD) exhibits antineoplastic activity in multiple GBM cell lines in culture and in xenograft mouse models (Massi et al, 2004(Massi et al, , 2006(Massi et al, , 2008Vaccani et al, 2005;Marcu et al, 2010;Torres et al, 2011;Nabissi et al, 2013;Solinas et al, 2013;Soroceanu et al, 2013). This antineoplastic activity is mediated through plasma membrane-associated receptors, including G protein-coupled receptor (GPR) 55 and transient receptor potential cation channel subfamily V member (TRPV) 1/2, and involves the production of reactive oxygen as well as induction of autophagy and apoptosis (Bisogno et al, 2001;Ligresti et al, 2006;Massi et al, 2006;Ford et al, 2010;Ramer et al, 2010;Yamada et al, 2010;Piñeiro et al, 2011;Anavi-Goffer et al, 2012).…”