Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. (May 2017)

• Record Type: Journal Article
• Authors: Pagano, Ester; Borrelli, Francesca; Orlando, Pierangelo; Romano, Barbara; Monti, Martina; Morbidelli, Lucia; Aviello, Gabriella; Imperatore, Roberta; Capasso, Raffaele; Piscitelli, Fabiana; Buono, Lorena; Di Marzo, Vincenzo; Izzo, Angelo A.
• Is Part Of: Pharmacological research. Volume 119(2017:May)
• Page Start: 227
• Page End: 236
• Publication Date: 2017-05
• Subjects: 2-AG 2-arachidonoyl glycerol -- ACF aberrant crypt foci -- AEA anandamide -- AOM azoxymethane -- BSA bovine serum albumin -- HCT116 colon adenocarcinoma cell line -- CRC colorectal cancer -- DMSO dimethyl sulphoxide -- DMEM Dulbecco's modified Eagle's medium -- EGM-2 endothelial growth medium-2 -- FAAH fatty acid amide hydrolase -- FCS fetal calf serum -- FGF-2 fibroblast growth factor-2 -- FBS foetal bovine serum -- HUVEC human umbilical vein endothelial cell line -- i.p. intraperitoneally -- MAGL monoacylglycerol lipase -- OEA oleoylethanolamide -- PEA palmitoylethanolamide -- PBS phosphate buffer solution -- TBS tris-buffered saline -- VEGF vascular endothelial growth factor; Cannabinoid receptor -- Colorectal cancer -- Cancer prevention -- Lipid metabolism; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2017.02.002
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells. Here, we investigated the role of MAGL in experimental colon carcinogenesis. The role of MAGL was assessed in vivo by using the xenograft and the azoxymethane models of colon carcinogenesis; MAGL expression was evaluated by RT-PCR and immunohistochemistry; 2-AG levels were measured by liquid chromatography mass spectrometry; angiogenesis was evaluated in tumor tissues [by microvessel counting and by investigating the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) proteins] as well as in human umbilical vein endothelial cells (HUVEC); cyclin D1 was evaluated by RT-PCR. MAGL and 2-AG were strongly expressed in tumor tissues. The MAGL inhibitor URB602 reduced xenograft tumor volume, this effect being associated to down-regulation of VEGF and FGF-2, reduction in the number of vessels and down-regulation of cyclin D1. In HUVEC, URB602 exerted a direct antiangiogenic effect by inhibiting FGF-2 induced proliferation and migration, and by modulating pro/anti-angiogenic agents. In experiments aiming at investigating the role of MAGL in chemoprevention, URB602 attenuated azoxymethane-induced preneoplastic lesions, polyps and tumors. MAGL, possibly through modulation of angiogenesis, plays a pivotal role in experimental colon carcinogenesis. Pharmacological inhibition of MAGL could represent an innovative therapeutic approach to reduce colorectal tumor progression.