Insight into the mode of action of phytocannabinoids against ovarian cancer and glioblastoma

Glioblastoma multiforme (GBM) is a subtype of glioma brain tumors and the most frequent, invasive, and lethal among them. Ovarian cancer (OC) is the most lethal gynecological malignancy and is frequently diagnosed only at an advanced stage. Cannabis sativa produces hundreds of phytocannabinoids, terpenes and flavonoids and is used worldwide mainly for palliative care. Δ9-trans-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG) and additional phytocannabinoids demonstrate anticancer activity against different cancer types in vitro and in vivo. However, no robust clinical trials have been completed confirming their efficacy in GBM or OC patients. In this literature review the mode of action underlying the anticancer activity of phytocannabinoids is discussed. We highlight similar tendencies in activation or repression of genetic pathways by phytocannabinoids in both OC and GBM cells. These include the following pathways: phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR), Wnt, rat sarcoma virus (RAS)– rapidly accelerated fibrosarcoma (RAF)–MAPK kinase (MEK)–extracellular signal-related kinase (ERK) (MAPK/ERK), c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK), transforming growth factor β (TGF-β) and Ras homolog (Rho)/Rho associated coiled-coil containing protein kinase (Rock) pathways. In addition, we discuss several translational challenges for phytocannabinoids. Overall, phytocannabinoids affect several molecular pathways that are key players in the progression of GBM and OC. This points to phytocannabinoids as an important subject of clinical investigation to determine if preclinical molecular effects can translate to clinical benefits.