Patsos H A, Hicks D J, Dobson R R H, Greenhough A, Woodman N, Lane J D, Williams A C, Paraskeva C
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.
Gut. 2005 Dec;54(12):1741-50. doi: 10.1136/gut.2005.073403. Epub 2005 Aug 11.
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.
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.
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.
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.
环氧化酶2（COX-2）在大多数结直肠癌中上调，负责将内源性大麻素花生四烯酸乙醇胺代谢为前列腺素乙醇酰胺（PG-EA）。本研究的目的是确定花生四烯酸乙醇胺和PG-EA是否能诱导结直肠癌（CRC）细胞死亡，以及CRC细胞中高水平的COX-2是否可被用于通过花生四烯酸乙醇胺对其进行特异性靶向细胞死亡。
我们通过测量细胞生长和细胞死亡来确定花生四烯酸乙醇胺对人CRC细胞生长的影响，这是否依赖于COX-2蛋白表达或酶活性，以及PG-EA在诱导细胞死亡中的潜在作用。
花生四烯酸乙醇胺抑制CRC细胞系HT29和HCA7/C29（分别为中度和高度COX-2表达者）的生长，但对极低COX-2表达的CRC细胞系SW480影响很小。COX-2选择性抑制剂NS398部分挽救了HT29和HCA7/C29细胞系中的细胞死亡诱导。花生四烯酸乙醇胺诱导的细胞死亡既不是凋亡也不是坏死。此外，抑制脂肪酸酰胺水解酶增强了非凋亡性细胞死亡，表明花生四烯酸乙醇胺诱导的细胞死亡是通过COX-2对花生四烯酸乙醇胺的代谢介导的，而不是其降解为花生四烯酸和乙醇胺。有趣的是，PGE2-EA和PGD2-EA均诱导经典凋亡。
这些发现表明，花生四烯酸乙醇胺可能是一种有用的结直肠癌化学预防/治疗剂，因为它靶向COX-2高表达的细胞，也可用于根除对凋亡产生抗性的肿瘤细胞。
