The endocannabinoid system in cancer biology: a mini-review of mechanisms and therapeutic potential

Abstract

The Endocannabinoid System (ECS) plays a critical role in maintaining physiological homeostasis, influencing a range of processes such as neuroprotection, inflammation, energy metabolism, and immune responses. Comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation, the ECS has attracted increasing attention in cancer research. Cannabinoid receptor activation has been associated with the regulation of cancer-related processes, including cell proliferation, apoptosis, and angiogenesis, suggesting that the ECS may have a role in tumor progression and cancer treatment. Preclinical studies have shown that cannabinoids, through their interaction with CB1 and CB2 receptors, can inhibit tumor cell growth, induce programmed cell death, and suppress the formation of new blood vessels in various cancer models. Despite these encouraging findings, the clinical translation of ECS-targeted therapies remains in its early stages. The complexity of tumor heterogeneity, the variability in patient responses, and the challenges associated with the pharmacokinetics of cannabinoids are significant obstacles to the broader application of these findings in clinical settings. This review provides an overview of the current understanding of the ECS's involvement in cancer biology, focusing on key mechanisms by which it may influence carcinogenesis. Additionally, we discuss the therapeutic potential of targeting the ECS in cancer treatment, while highlighting the limitations and uncertainties that need to be addressed through ongoing research.

Keywords: apoptosis; cancer biology; cannabinoid receptors; endocannabinoid system; tumor angiogenesis.

FIGURE 1

Schematic representation highlighting the diverse physiological roles of cannabinoid receptors CB1 and CB2. CB1, primarily distributed within the central nervous system, modulates reward pathways, motor coordination, pain perception, appetite regulation, and energy homeostasis, alongside exerting anti-inflammatory actions. Meanwhile, CB2, predominantly expressed in immune cells, regulates immune responses, mitigates excessive inflammation, influences liver fibrosis, and governs immune function within the central nervous system, in addition to controlling the production of reactive oxygen species (ROS). These functions underscore the pivotal involvement of CB1 and CB2 in both neurological and immunological processes, with ongoing investigations poised to reveal further intricacies and therapeutic potentials associated with these receptors.

FIGURE 2

Classical pathways involved in the biosynthesis and degradation of endocannabinoids Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG). (A) Biosynthesis and degradation of AEA: The biosynthesis of AEA begins with the transfer of an acyl group (commonly arachidonic acid) from Phosphatidylcholine (PC) to Phosphatidylethanolamine (PE), catalyzed by an N-acyltransferase, resulting in the formation of N-Arachidonoyl phosphatidylethanolamine (NAPE). Subsequently, NAPE is hydrolyzed by NAPE-specific phospholipase D (NAPE-PLD) to produce Anandamide (AEA). AEA is then degraded by fatty acid amide hydrolase (FAAH) into arachidonic acid and ethanolamine. (B) Biosynthesis and degradation of 2-AG: The biosynthesis of 2-AG involves the hydrolysis of Phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C-β (PLC-β), yielding diacylglycerol (DAG). DAG is then converted into 2-Arachidonoylglycerol (2-AG) by diacylglycerol lipase (DAGL). Finally, 2-AG is degraded by monoacylglycerol lipase (MAGL) into arachidonic acid and glycerol.