COLORECTAL CANCER

The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2

H A Patsos¹, D J Hicks¹, R R H Dobson¹, A Greenhough¹, N Woodman¹, J D Lane², A C Williams¹ and C Paraskeva¹

¹ Cancer Research UK Colorectal Tumour Biology Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, UK
² Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK

Correspondence to:
Correspondence to:
Professor C Paraskeva
Cancer Research UK Colorectal Tumour Biology Group, Department of Pathology and Microbiology, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK; C.Paraskeva{at}bristol.ac.uk

Background and aims: Cyclooxygenase 2 (COX-2) is upregulated in most colorectal cancers and is responsible for metabolism of the endogenous cannabinoid, anandamide, into prostaglandin-ethanolamides (PG-EAs). The aims of this study were to determine whether anandamide and PG-EAs induce cell death in colorectal carcinoma (CRC) cells, and whether high levels of COX-2 in CRC cells could be utilised for their specific targeting for cell death by anandamide.

Methods: We determined the effect of anandamide on human CRC cell growth by measuring cell growth and cell death, whether this was dependent on COX-2 protein expression or enzyme activity, and the potential involvement of PG-EAs in induction of cell death.

Results: Anandamide inhibited the growth of CRC cell lines HT29 and HCA7/C29 (moderate and high COX-2 expressors, respectively) but had little effect on the very low COX-2 expressing CRC cell line, SW480. Induction of cell death in HT29 and HCA7/C29 cell lines was partially rescued by the COX-2 selective inhibitor NS398. Cell death induced by anandamide was neither apoptosis nor necrosis. Furthermore, inhibition of fatty acid amide hydrolase potentiated the non-apoptotic cell death, indicating that anandamide induced cell death was mediated via metabolism of anandamide by COX-2, rather than its degradation into arachidonic acid and ethanolamine. Interestingly, both PGE₂-EA and PGD₂-EA induced classical apoptosis.

Conclusions: These findings suggest anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the eradication of tumour cells that have become resistant to apoptosis.

Abbreviations: ⁹-THC, ⁹-tetrahydrocannabinol; AEA, arachidonoyl ethanolamine (anandamide); CB, cannabinoid; COX, cyclooxygenase; CRC, colorectal carcinoma; FAAH, fatty acid amide hydrolase; FBS, fetal bovine serum; HRP, horseradish peroxidase; PG, prostaglandin; PG-EA, prostaglandin-ethanolamide; PI, propidium iodide; RT-PCR, reverse transcriptase-polymerase chain reaction

Keywords: cannabinoid; anandamide; colorectal carcinoma; cyclooxygenase-2; fatty acid amide hydrolase; cell death

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Cianchi, F., Papucci, L., Schiavone, N., Lulli, M., Magnelli, L., Vinci, M. C., Messerini, L., Manera, C., Ronconi, E., Romagnani, P., Donnini, M., Perigli, G., Trallori, G., Tanganelli, E., Capaccioli, S., Masini, E. (2008). Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor {alpha}-Mediated Ceramide De novo Synthesis in Colon Cancer Cells. Clin. Cancer Res. 14: 7691-7700 [Abstract] [Full Text]  
• Izzo, A A, Camilleri, M (2008). Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut 57: 1140-1155 [Abstract] [Full Text]  
• Kaidi, A., Qualtrough, D., Williams, A. C., Paraskeva, C. (2006). Direct Transcriptional Up-regulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 Promotes Colorectal Tumor Cell Survival and Enhances HIF-1 Transcriptional Activity during Hypoxia.. Cancer Res. 66: 6683-6691 [Abstract] [Full Text]