Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon.
J Mol Med. 2007-09-06; 86(1): 89-98
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1. J Mol Med (Berl). 2008 Jan;86(1):89-98. Epub 2007 Sep 6.
Increased endocannabinoid levels reduce the development of precancerous lesions
in the mouse colon.
Izzo AA(1), Aviello G, Petrosino S, Orlando P, Marsicano G, Lutz B, Borrelli F,
Capasso R, Nigam S, Capasso F, Di Marzo V; Endocannabinoid Research Group.
(1)Department of Experimental Pharmacology, University of Naples Federico II,
Colorectal cancer is an increasingly important cause of death in Western
countries. Endocannabinoids inhibit colorectal carcinoma cell proliferation in
vitro. In this paper, we investigated the involvement of endocannabinoids on the
formation of aberrant crypt foci (ACF, earliest preneoplastic lesions) in the
colon mouse in vivo. ACF were induced by azoxymethane (AOM); fatty acid amide
hydrolase (FAAH) and cannabinoid receptor messenger ribonucleic acid (mRNA)
levels were analyzed by the quantitative reverse transcription polymerase chain
reaction (RT-PCR); endocannabinoid levels were measured by liquid
chromatography-mass spectrometry; caspase-3 and caspase-9 expressions were
measured by Western blot analysis. Colonic ACF formation after AOM administration
was associated with increased levels of 2-arachidonoylglycerol (with no changes
in FAAH and cannabinoid receptor mRNA levels) and reduction in cleaved caspase-3
and caspase-9 expression. The FAAH inhibitor N-arachidonoylserotonin increased
colon endocannabinoid levels, reduced ACF formation, and partially normalized
cleaved caspase-3 (but not caspase-9) expression. Notably,
N-arachidonoylserotonin completely prevented the formation of ACF with four or
more crypts, which have been show to be best correlated with final tumor
incidence. The effect of N-arachidonoylserotonin on ACF formation was mimicked by
the cannabinoid receptor agonist HU-210. No differences in ACF formation were
observed between CB(1) receptor-deficient and wild-type mice. It is concluded
that pharmacological enhancement of endocannabinoid levels (through inhibition of
endocannabinoid hydrolysis) reduces the development of precancerous lesions in
the mouse colon. The protective effect appears to involve caspase-3 (but not
PMID: 17823781 [Indexed for MEDLINE]