title: Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis.
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.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Pagano
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: franborr@unina.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Borrelli
authors.affiliation: Institute of Protein Biochemistry, Naples, Italy; Institute of Applied Sciences & Intelligent Systems, National Research Council, Pozzuoli (NA), Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Romano
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Monti
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy; The Rowett Institute, University of Aberdeen, Aberdeen, Scotland, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Aviello
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.affiliation: Department of Agricultural Sciences, University of Naples Federico II, Portici, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Capasso
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy; Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-UAM, 28049, Cantoblanco, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Buono
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy. Electronic address: vdimarzo@icb.cnr.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Izzo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000378:metabolism; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003106:Colon / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005989:Glycerides / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012007:Rectum / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C501835:URB602; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: Cancer prevention; Cannabinoid receptor; Colorectal cancer; Lipid metabolism