Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis

Ester Pagano, Francesca Borrelli (Corresponding Author), Pierangelo Orlando, Barbara Romano, Martina Monti, Lucia Morbidelli, Gabriella Aviello, Roberta Imperatore, Raffaele Capasso, Fabiana Piscitelli, Lorena Buono, Vincenzo Di Marzo, Angelo A Izzo

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)227-236
Number of pages10
JournalPharmacological Research
Volume119
Early online date11 Feb 2017
DOIs
Publication statusPublished - May 2017

Fingerprint

Monoacylglycerol Lipases
Colon
Carcinogenesis
Pharmacology
Fibroblast Growth Factor 2
Azoxymethane
Colorectal Neoplasms
Cyclin D1
Human Umbilical Vein Endothelial Cells
Heterografts
Vascular Endothelial Growth Factor A
Neoplasms
Down-Regulation
Polymerase Chain Reaction
Endocannabinoids
Chemoprevention
Hydrolases
Polyps
Microvessels
Tumor Burden

Keywords

  • cannabinoid receptor
  • colorectal cancer
  • cancer prevention
  • lipid metabolism

Cite this

Pagano, E., Borrelli, F., Orlando, P., Romano, B., Monti, M., Morbidelli, L., ... Izzo, A. A. (2017). Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacological Research, 119, 227-236. https://doi.org/10.1016/j.phrs.2017.02.002

Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. / Pagano, Ester; Borrelli, Francesca (Corresponding Author); Orlando, Pierangelo; Romano, Barbara; Monti, Martina; Morbidelli, Lucia; Aviello, Gabriella; Imperatore, Roberta; Capasso, Raffaele; Piscitelli, Fabiana; Buono, Lorena; Di Marzo, Vincenzo; Izzo, Angelo A.

In: Pharmacological Research, Vol. 119, 05.2017, p. 227-236.

Research output: Contribution to journalArticle

Pagano, E, Borrelli, F, Orlando, P, Romano, B, Monti, M, Morbidelli, L, Aviello, G, Imperatore, R, Capasso, R, Piscitelli, F, Buono, L, Di Marzo, V & Izzo, AA 2017, 'Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis', Pharmacological Research, vol. 119, pp. 227-236. https://doi.org/10.1016/j.phrs.2017.02.002
Pagano E, Borrelli F, Orlando P, Romano B, Monti M, Morbidelli L et al. Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacological Research. 2017 May;119:227-236. https://doi.org/10.1016/j.phrs.2017.02.002
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. / Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. In: Pharmacological Research. 2017 ; Vol. 119. pp. 227-236.
@article{18748a23ec894f60b038a322a82c49a9,
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.",
keywords = "cannabinoid receptor, colorectal cancer, cancer prevention, lipid metabolism",
author = "Ester Pagano and Francesca Borrelli and Pierangelo Orlando and Barbara Romano and Martina Monti and Lucia Morbidelli and Gabriella Aviello and Roberta Imperatore and Raffaele Capasso and Fabiana Piscitelli and Lorena Buono and {Di Marzo}, Vincenzo and Izzo, {Angelo A}",
note = "This work was partly supported by MIUR-PRIN funding (to L.M.) and ADLER PLASTIC SPA.",
year = "2017",
month = "5",
doi = "10.1016/j.phrs.2017.02.002",
language = "English",
volume = "119",
pages = "227--236",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis

AU - Pagano, Ester

AU - Borrelli, Francesca

AU - Orlando, Pierangelo

AU - Romano, Barbara

AU - Monti, Martina

AU - Morbidelli, Lucia

AU - Aviello, Gabriella

AU - Imperatore, Roberta

AU - Capasso, Raffaele

AU - Piscitelli, Fabiana

AU - Buono, Lorena

AU - Di Marzo, Vincenzo

AU - Izzo, Angelo A

N1 - This work was partly supported by MIUR-PRIN funding (to L.M.) and ADLER PLASTIC SPA.

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - cannabinoid receptor

KW - colorectal cancer

KW - cancer prevention

KW - lipid metabolism

U2 - 10.1016/j.phrs.2017.02.002

DO - 10.1016/j.phrs.2017.02.002

M3 - Article

C2 - 28193521

VL - 119

SP - 227

EP - 236

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

ER -