The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

Abstract

Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.

The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

“…A number of different cannabinoids have shown antitumour effects in many preclinical studies when applied individually (for review see [1,2]). In the present study, the combination of THC and CBD showed a synergistic inhibitory effect on the viability of human glioblastoma cells at 5 µM each, and can therefore be considered as a promising add-on therapy for glioblastoma, which is in agreement with the studies of other authors [6][7][8][9][10][11].…”

“…Soon after, a growth inhibitory effect on glioma xenografts was confirmed for the selective cannabinoid receptor CB 2 agonist JWH-133 [5]. In the meantime, cannabinoid-mediated anticancer effects have also been demonstrated in a variety of other tumour entities, whereby the effects shown here range from the initially demonstrated inhibition of proliferation and induction of tumour cell apoptosis to proautophagic, anti-angiogenic, anti-invasive and antimetastatic effects (for review see [1,2]).…”

“…Over the past two decades, a large number of extensive preclinical studies have shown that cannabinoids of plant, synthetic and endogenous origin can inhibit tumourigenesis and 2 of 22 tumour spread (for review [1,2]). Studies on the effect of cannabinoids on glioma cells have been published particularly frequently, and are of great importance in that glioblastoma multiforme or astrocytoma grade IV, an extremely aggressive cancer, has a high resistance to radiation and standard chemotherapy (for review [3]).…”

Impact of Cannabinoid Compounds on Skin Cancer

“…Notably, the latter study included only 21 patients. Interestingly, there are several other studies currently listed in the U.S. National Library of Medicine’s registry on the website that addressed the systemic effects of cannabinoids in cancer patients (for a review, see [ 131 ]). However, none of the registered studies focused on cannabinoids as a potential option for the systemic treatment of skin cancer.…”

Targeting the Endocannabinoidome in Pancreatic Cancer

“…The use of molecules interfering with endocannabinoid-metabolising enzymes represents an intriguing additional therapeutic strategy. A recent review summarised the relevant preclinical studies with FAAH and MAGL inhibitors in cancer [ 107 ]. This field of investigation is still in its infancy and more studies are required to explore fully the potential of interfering with enzymes responsible for endocannabinoids’ metabolism in cancer settings.…”