Possible endocannabinoid control of colorectal cancer growth

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
Gastroenterology. 2003-09-01; 125(3): 677-687
DOI: 10.1016/S0016-5085(03)00881-3

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1. Gastroenterology. 2003 Sep;125(3):677-87. doi: 10.1016/s0016-5085(03)00881-3.

Possible endocannabinoid control of colorectal cancer growth.

Ligresti A(1), Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V,
D’argenio G, Scaglione G, Bifulco M, Sorrentini I, Di Marzo V.

Author information:
(1)Endovannabinoid Research Group, Institute of Biomolecular Chemistry,
Pozzuoli, Italy.

Comment in
Gastroenterology. 2003 Sep;125(3):973-5.

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.

DOI: 10.1016/s0016-5085(03)00881-3
PMID: 12949714 [Indexed for MEDLINE]

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