Document Detail


Possible endocannabinoid control of colorectal cancer growth.
MedLine Citation:
PMID:  12949714     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit cancer cell proliferation by acting at cannabinoid receptors (CBRs). We studied (1). the levels of endocannabinoids, cannabinoid CB(1) and CB(2) receptors, and fatty acid amide hydrolase (FAAH, which catalyzes endocannabinoid hydrolysis) in colorectal carcinomas (CRC), adenomatous polyps, and neighboring healthy mucosa; and (2). the effects of endocannabinoids, and of inhibitors of their inactivation, on human CRC cell proliferation. METHODS: Tissues were obtained from 21 patients by biopsy during colonoscopy. Endocannabinoids were measured by liquid chromatography-mass spectrometry (LC-MS). CB(1), CB(2), and FAAH expression were analyzed by RT-PCR and Western immunoblotting. CRC cell lines (CaCo-2 and DLD-1) were used to test antiproliferative effects. RESULTS: All tissues and cells analyzed contain anandamide, 2-AG, CBRs, and FAAH. The levels of the endocannabinoids are 3- and 2-fold higher in adenomas and CRCs than normal mucosa. Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation. Inhibitors of endocannabinoid inactivation enhance CaCo-2 cell endocannabinoid levels and block cell proliferation, this effect being antagonized by SR141716A. CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids. CONCLUSIONS: Endocannabinoid levels are enhanced in transformed colon mucosa cells possibly to counteract proliferation via CBRs. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.
Authors:
Alessia Ligresti; Tiziana Bisogno; Isabel Matias; Luciano De Petrocellis; Maria Grazia Cascio; Vittorio Cosenza; Giuseppe D'argenio; Giuseppe Scaglione; Maurizio Bifulco; Italo Sorrentini; Vincenzo Di Marzo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Gastroenterology     Volume:  125     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-01     Completed Date:  2003-10-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  677-87     Citation Subset:  AIM; IM    
Affiliation:
Endovannabinoid Research Group, Institute of Biomolecular Chemistry, Pozzuoli, Italy.
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MeSH Terms
Descriptor/Qualifier:
Amidohydrolases / metabolism
Caco-2 Cells
Cell Differentiation
Cell Division
Colorectal Neoplasms / pathology*,  therapy
Cyclooxygenase 2
Endocannabinoids
Fatty Acids, Unsaturated / analysis,  antagonists & inhibitors,  physiology*
Humans
Isoenzymes / analysis,  antagonists & inhibitors
Membrane Proteins
Prostaglandin-Endoperoxide Synthases / analysis
Receptors, Cannabinoid
Receptors, Drug / analysis
Chemical
Reg. No./Substance:
0/Endocannabinoids; 0/Fatty Acids, Unsaturated; 0/Isoenzymes; 0/Membrane Proteins; 0/Receptors, Cannabinoid; 0/Receptors, Drug; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase
Comments/Corrections
Comment In:
Gastroenterology. 2003 Sep;125(3):973-5   [PMID:  12949741 ]

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