Abstract
Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoid receptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.
Highlights
The endocannabinoid system encompasses the two “classical” endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), and the cannabinoid receptors CB1 and CB2
↔, not regulated; ↑, upregulated; ↓, downregulated; a, measured in patients’ serum; b, associated with advanced disease stages; c, measured in patients’ plasma; d, endocannabinoids measured in plasma from breast, prostate, lung, pancreatic, skin, hematological, gynecological, and other unnamed cancers; 2-AG, 2-arachidonoylglycerol; 2-OG, 2-oleoylglycerol; AEA, N-arachidonoylethanolamine; OEA, N-oleoylethanolamine; PEA, N-palmitoylethanolamine; SEA, N-stearoylethanolamine
GPR55 was found to be activated by the synthetic regioisomer of CBD, abnormal-CBD, the specific GPR55 agonist structurally related to cannabinoids, O-1602, as well as by R(+)-methanandamide, 9-THC and the specific CB2 receptor agonist JWH-015 (Johns et al, 2007; Lauckner et al, 2008)
Summary
As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.”. Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acidbinding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferatoractivated receptors were identified as targets for possible strategies to combat cancer progression.
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