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

Helena A Patsos ¹, Diane J Hicks ¹, Richard R H Dobson ¹, Alexander Greenhough ¹, Natasha Woodman ¹, Jon D Lane ¹, Ann C Williams ¹ and Chris Paraskeva ^1*

¹ University of Bristol, United Kingdom

^* To whom correspondence should be addressed. E-mail: c.paraskeva{at}bristol.ac.uk.

Accepted 5 July 2005

Abstract

Background and Aims: Cyclooxygenase-2 (COX-2) is up-regulated 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 the high levels of COX-2 in CRC cells could be utilized 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 the 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 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 (FAAH) potentiated the non-apoptotic cell death, indicating that anandamide induced cell death was mediated via the 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, since anandamide 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.

Keywords: arachidonoylethanolamide (anandamide), cannabinoid, cell death, colorectal carcinoma, cyclooxygenase-2

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