Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities

Abstract

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.

Keywords: cancer; cancer stem cells; cannabinoid receptors; cannabis; cytotoxicity; glioblastoma; glioma; phytocannabinoids; synergy.

Figure 1

The main molecular mechanisms underlying the anti-tumor effects of C. sativa phytocannabinoids on glioma cells and glioblastoma stem cells. Phytocannabinoids inhibit cell viability and motility through various cannabinoid receptor (CB)-mediated mechanisms. THC acts as an agonist of both CB1 and CB2 receptors; CBD may act as a CB1 antagonist. The activation of CB1 or CB2 stimulates the synthesis and accumulation of ceramides (orange shape) and, as a result, triggers the induction of p8. This leads to the inhibition of cell migration and invasion through the downregulation of MMPs. Furthermore, p8 promotes the upregulation of ER-stress-related genes ATF-4, CHOP, and TRIB-3, followed by inhibition of the Akt-mTORC1 axis and initiation of autophagy, which is upstream of apoptosis. In addition, inhibition of Akt leads to the overexpression of BAD and consequently induces apoptosis via the intrinsic mitochondrial pathway. Another signaling pathway activated by ceramides is p38-MAPK, which involves both apoptosis activation and inhibition of CSC self-renewal through the downregulation of stemness regulators, such as p-STAT3, Id1, and Sox2 (yellow shapes). Green arrows represent upregulation and red arrows represent downregulation of biological processes. Purple shapes represent genes or proteins, and blue shapes represent biological processes.

Figure 2

Conceptual perspective of the anti-cancer activity of phytocannabinoids. Cannabis compounds and phytocannabinoids, in particular, by activating cannabinoid receptor-dependent mechanisms, may interact synergistically in some of the cases and target malignant cells by inducing, e.g., cell apoptosis and inhibition of cancer cell migration. Moreover, phytocannabinoids may target CSCs, in some cases leading to an improved outcome, e.g., by inhibiting the characteristic self-renewal and drug resistance of CSCs.