Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon

Angelo A Izzo, Gabriella Aviello, Stefania Petrosino, Pierangelo Orlando, Giovanni Marsicano, Beat Lutz, Francesca Borrelli, Raffaele Capasso, Santosh Nigam, Francesco Capasso, Vincenzo Di Marzo, Endocannabinoid Research Group

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Abstract

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 caspase-9) activation.

Original languageEnglish
Pages (from-to)89-98
Number of pages10
JournalJournal of Molecular Medicine
Volume86
Issue number1
Early online date6 Sep 2007
DOIs
Publication statusPublished - Jan 2008

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Keywords

  • Amidohydrolases
  • Animals
  • Azoxymethane
  • Cannabinoid Receptor Modulators
  • Caspase 3
  • Caspase 9
  • Colon
  • Colonic Neoplasms
  • Endocannabinoids
  • Mass Spectrometry
  • Mice
  • Precancerous Conditions
  • RNA, Messenger
  • Receptors, Cannabinoid
  • Reverse Transcriptase Polymerase Chain Reaction
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Izzo, A. A., Aviello, G., Petrosino, S., Orlando, P., Marsicano, G., Lutz, B., ... Endocannabinoid Research Group (2008). Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. Journal of Molecular Medicine, 86(1), 89-98. https://doi.org/10.1007/s00109-007-0248-4