Cannabigerol Is a Potential Therapeutic Agent in a Novel Combined Therapy for Glioblastoma

SIMPLE SUMMARY: Among primary brain tumours, glioblastoma is the most aggressive. As early relapses are unavoidable despite standard-of-care treatment, the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone or in combination have been suggested as a combined treatment strategy for glioblastomas. However, the known psychoactive effects of THC hamper its medical applications in these patients with potential cognitive impairment due to the progression of the disease. Therefore, nontoxic cannabigerol (CBG), being recently shown to exhibit anti-tumour properties in some carcinomas, is assayed here for the first time in glioblastoma with the aim to replace THC. We indeed found CBG to effectively impair the relevant hallmarks of glioblastoma progression, with comparable killing effects to THC and in addition inhibiting the invasion of glioblastoma cells. Moreover, CBG can destroy therapy-resistant glioblastoma stem cells, which are the root of cancer development and extremely resistant to various other treatments of this lethal cancer. CBG should present a new yet unexplored adjuvant treatment strategy of glioblastoma. ABSTRACT: Glioblastoma is the most aggressive cancer among primary brain tumours. As with other cancers, the incidence of glioblastoma is increasing; despite modern therapies, the overall mean survival of patients post-diagnosis averages around 16 months, a figure that has not changed in many years. Cannabigerol (CBG) has only recently been reported to prevent the progression of certain carcinomas and has not yet been studied in glioblastoma. Here, we have compared the cytotoxic, apoptotic, and anti-invasive effects of the purified natural cannabinoid CBG together with CBD and THC on established differentiated glioblastoma tumour cells and glioblastoma stem cells. CBG and THC reduced the viability of both types of cells to a similar extent, whereas combining CBD with CBG was more efficient than with THC. CBD and CBG, both alone and in combination, induced caspase-dependent cell apoptosis, and there was no additive THC effect. Of note, CBG inhibited glioblastoma invasion in a similar manner to CBD and the chemotherapeutic temozolomide. We have demonstrated that THC has little added value in combined-cannabinoid glioblastoma treatment, suggesting that this psychotropic cannabinoid should be replaced with CBG in future clinical studies of glioblastoma therapy.