Title

 

Authors

G. Aviello¹, B. Romano¹, F. Borrelli¹, R. Capasso¹,  F. Piscitelli², P. Orlando³, S. Pace¹, F. Capasso¹, V. Di Marzo², A.A. Izzo<sup>1

1</sup>Dept. of Experimental Pharmacology, University of Naples Federico II, Naples Italy; ²Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy; ³Institute of Cybernetics, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy; Endocannabinoid Research Group.

 

Abstract

Background and Purpose Many studies have been published on the role of the endocannabinoid system (ECS) in  several types of cancer (Guindon and Hohmann, 2011). However, the role of the ECS in colon cancer is still largely unexplored (Izzo and Sharkey, 2010). This study was therefore aimed at 1) providing insights into the role of the ECS in chemically-induced colon cancer in vivo and 2) evaluating the potential chemopreventive effect of cannabidiol (CBD, a non-psychotropic phytocannabinoid) (Izzo et al., 2009) on colon cancer both in vivo and in vitro. Methods Aberrant crypt foci (ACF), polyps and tumours were induced in mice by azoxymethane (AOM); receptors and proteins of the ECS were analyzed by quantitative RT-PCR; endocannabinoid levels by HPLC-MS; iNOS, COX-2, phosphoAkt, and caspase-3 by western blot analysis. Cell proliferation was evaluated in human colon adenocarcinoma cell lines using trypan blue staining, MTT assay and ³H-thymidine incorporation. Key results AOM administration resulted in the formation of ACF, polyps, tumours, increased endocannabinoid levels, changes in proteins of the ECS, up-regulation of iNOS, COX-2 and phosphoAkt, and down-regulation of caspase-3 expression. The CB1 agonist ACEA - but not the CB2 receptor agonist JHW033 - and CBD reduced ACF, polyps and tumours. CBD counteracted phosphoAkt and caspase-3 (but not COX-2 or iNOS) changes induced by AOM. In vitro, CBD reduced cell proliferation in a CB1-, TRPV1- and PPAR-γ-antagonist sensitive manner. Conclusions The colonic ECS undergoes adaptive changes in response to the carcinogenic agent AOM. CBD, which reduces tumour formation in vivo and cell proliferation through multiple pharmacological mechanisms, may represent a new potential chemopreventive agent for colon carcinogenesis.

Guindon and Hohmann (2011). Br J Pharmacol. Mar 15 [Epub ahead of print].
Izzo and Sharkey (2010). Pharmacol Ther. 126,21-38.
Izzo et al. (2009). Trends Pharmacol Sci. 30,515-27