Insights into the effects of the endocannabinoid system in cancer: a review

Abstract

In the last few decades, the endocannabinoid system has attracted a great deal of interest in terms of its applications to clinical medicine. In particular, its applications in cancer probably represent one of the therapeutic areas with most promise. On the one hand, expression of the endocannabinoid system is altered in numerous types of tumours, compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and disease outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type. On the other hand, cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells and also tumour angiogenesis. However, some cannabinoids, at lower concentrations, may increase tumour proliferation, inducing cancer growth. Enough data has been provided to consider the endocannabinoid system as a new therapeutic target in cancer, although further studies to fully establish the effect of cannabinoids on tumour progression are still needed.

Figure 1

Diagram showing the main biosynthetic and degradation pathways of both AEA and 2‐AG. Anandamide is synthesized via a phospholipase‐D (NAPE‐PLD), which converts N‐arachidonoylphosphatidylethanolamine (NAPE), formed by the transfer of an arachidonoyl group to phosphatidylethanolamine by the action of N‐acetyltransferase (NAT), to AEA. 2‐AG is formed from diacylglycerol, via diacylglycerol lipase (DGL). Diacylglycerol is synthesized from phosphatidylinositol by the action of a PLC. In terms of degradation pathways, FAAH and MAGL are the most important enzymes responsible for inactivation of AEA and 2‐AG respectively. However, other pathways also participate in their degradation including lipoxygenases, cytochrome P450, COX‐2 and the domains 6 and 12 of serine lipases a/ß hydrolases.

Figure 2

Altered expression of endocannabinoid system in brain, breast, digestive tract, gynaecological and prostate carcinomas.