Potentiation of endocannabinoid antitumoral properties by inhibitors of their hydrolysis
(2012)
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- (en) Since the identification of the ∆9-tetrahydrocannabinol as the main psychoactive component of the plant Cannabis sativa, a notable amount of studies have been carried out in order to elucidate the implication of the so-called endocannabinoid system in health and various diseases. This system is composed of endogenous bioactive lipids, principally anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which activate the CB1 and CB2 cannabinoid receptors. Additionally, these endocannabinoids have also been described to activate other plasma membrane proteins like the vanilloid type 1 receptor (TRPV1), two G protein-coupled receptors – GPR55 and GPR119 – as well as peroxisome proliferator-activated receptors (PPAR’s). Along with the endocannabinoids, other endogenous molecules belonging to the N-acylethanolamine family, including N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), are known to exert cannabimimetic actions without binding the cannabinoid receptors. These “endocannabinoid-like” share with AEA common metabolic pathways as well as some molecular targets. Endocannabinoid levels are tightly regulated by enzymes responsible for their degradation. The fatty acid amide hydrolase (FAAH) and the N-acylethanolamine-hydrolyzing acid amidase (NAAA) are in charge of the hydrolysis the N-acylethanolamines AEA, PEA and OEA, while the major enzyme regulating 2-AG levels is the monoacylglycerol lipase (MAGL). Cancer is one of the main causes of death worldwide and a major health care challenge. During the last few years, the involvement of the endocannabinoids in antitumoral processes received a particular attention and evidence has accumulated to demonstrate the ability of cannabinoids to decrease proliferation and viability in numerous cancer cell lines both in vitro and in vivo. The present work intends to investigate the influence of the endocannabinoids AEA and 2-AG, as well as PEA and OEA, on tumor cell proliferation and survival. Selective endocannabinoid hydrolyzing enzyme inhibitors served as useful probes to explore the function and potentiate the action of these lipid mediators. We focused on two mouse cancer models: N1E-115 neuroblastoma and B16 melanoma. We further highlighted the interest of targeting the endocannabinoid system in the management of cancer and evidenced the cytotoxic effects of endocannabinoids in both cell lines. In neuroblastoma cells, the most cytotoxic treatment was achieved by the co-incubation of AEA with the selective FAAH inhibitor URB597. This compound drastically reduced cell viability, partly due to the inhibition of AEA hydrolysis and the resulting increase in AEA levels. We found that this combination decreased cell proliferation and slowed cell cycle progression without inducing cell death. In contrast, the association of PEA with URB597 synergistically induced melanoma cell death. The effect was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. This antitumor action was associated with an elevation of PEA levels and larger necrotic regions in the tumor. The targets mediating the antiproliferative effects of AEA and URB597 on neuroblastoma cells and those responsible for the decrease of cell survival induced by PEA and URB597 on melanoma cells are still conflicting and remain to be further investigated. Though our results suggest a mechanism independent of the activation of cannabinoid, TRPV1, PPARs and GPR55 receptors in both cancer models, it seems to occur through a lipid raft-dependent pathway in the case of neuroblastoma. There is still a long way to go until the introduction of endocannabinoids in the therapeutic arsenal against cancer progression. However, this work emphasizes the great potential benefit of associating endocannabinoids with enzymatic hydrolysis inhibitors for the development of novel anticancer therapies.
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Hamtiaux, L. (2012). Potentiation of endocannabinoid antitumoral properties by inhibitors of their hydrolysis. https://hdl.handle.net/2078.5/39541