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COLORECTAL CANCER |
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
ABSTRACT
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
This article has been cited by other articles:
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  A A Izzo and M Camilleri Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects Gut, August 1, 2008; 57(8): 1140 - 1155. [Abstract] [Full Text] [PDF]
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