Abstract
Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation. Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA. We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation. The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production.
Highlights
Cannabinoids have been recently proposed as a new family of potential antitumor agents
The regulation of the RAS – mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the phosphatidylinositol 3-kinase – AKT pathways and the stimulation of ceramide synthesis are among the mechanisms proposed to explain the antitumor effects of cannabinoids in different types of human cancer
We report that both CB1 and CB2 cannabinoid receptor activation induces apoptosis in colon cancer cells, and this is mediated by the de novo synthesis of ceramide
Summary
Cannabinoids have been recently proposed as a new family of potential antitumor agents. Conclusions: The present study shows that either CB1or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. The present study shows that the antitumor actions of cannabinoid receptor agonists on colon cancer cells may be exerted either via the CB1 receptor or, more efficiently, via the CB2 receptor. The fact that selective targeting of CB2 receptor results in colorectal tumor growth inhibition is of potential clinical interest for future cannabinoid-based anticancer therapies because the use of CB2-selective ligands is not linked to the typical marijuana-like psychoactive effects of CB1 activation. We showed that only the CB2 receptor is expressed by tumor cells in colorectal cancer human specimens and, it is likely that only compounds with high selectivity for this receptor may be effective as anticancer agents in humans. The recent synthesis of new, highly selective CB2 agonists [18] opens the very attractive clinical possibility of targeting this receptor selectively
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