Abstract
Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.
Highlights
The flowering herb Cannabis sativa L. (Cannabaceae) has been used in traditional Eastern medicines as an analgesic, anxiolytic, anticonvulsant, sedative, and hypnotic, for almost 5000 years [1]
cannabinoid receptors (CBRs) activation by either ∆9 -THC or WIN-55,212-2 drives the intracellular accumulation of ceramide to activate Raf1/extracellular signal-regulated kinases (ERK) signalling, which in turn leads to the production of damaging cellular reactive oxygen species (ROS) (Figures 2 and 3)
The overlap between apoptosis and autophagy is potentially regulated by Beclin-1 (BECN1); CBD enhanced the interaction between BECN1 and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), as this protein-protein interaction cross-regulates the instigation of autophagosomes, and the activation of apoptosis, through direct interactions with anti-apoptosis family members Bcl-2 and/or Bcl-xL
Summary
The flowering herb Cannabis sativa L. (Cannabaceae) has been used in traditional Eastern medicines as an analgesic, anxiolytic, anticonvulsant, sedative, and hypnotic, for almost 5000 years [1]. The recent rapid change to the legislative status of recreational and medicinal cannabis is enabling appropriate assessment of the use of cannabis and cannabinoids in the clinical setting [4]. The more recently reported positive health benefits of CBD, and for other non-THC cannabinoids, has promoted and accelerated research into non-THC cannabinoids [11,12,13]. In spite of these promising findings, legislation continues to lag. There is currently limited evidence regarding the long-term safety and cognitive consequences of the sustained consumption of CBD, either in the recreational or medicinal setting [36]
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