Studies on the Effects of Plant and Food Constituents on Cyclooxygenase-2 : Aspects in Inflammation and Cancer
In inflammatory events, the cyclooxygenase-2 enzyme (COX-2) catalyses prostaglandin biosynthesis. This is a process, which could possibly be affected by natural compounds including those abundant in food. Two systems have been established to enable investigations of the effects of natural compounds on COX-2. The first method developed was an in vitro method suitable for measuring inhibition of COX-2 catalysed prostaglandin E2 biosynthesis, based on scintillation proximity assay technology. The second system established, comprises a cell model, suitable for studying the effects of compounds on COX-2 and inducible nitric oxide synthase (iNOS) at different cellular levels, including the effects on mRNA, protein, prostaglandin E2 and nitrite levels.The plants, Plantago major L. and Urtica dioica L., were subjected to bioassay-guided isolation and fatty acids, e.g. ?-linolenic acid and linoleic acid, were isolated as COX-2 inhibitory principles. The effects of structurally related fatty acids were also studied and the most potent COX-2 inhibitors were eicosapentaenoic acid and its synthetic derivative all-(Z) -5-thia-8,11,14,17-eicosatetraenoic acid. The latter was also found to decrease COX-2 protein levels assessed by the cell model. The inhibitory effects on COX-2 catalysed prostaglandin biosynthesis of 49 plant metabolites with different biosynthetic origin were studied. The phenolic compounds, eugenol, pyrogallol, but also cinnamaldehyde, were found to inhibit COX-2.Recently, COX-2 has attracted attention because of its involvement in cancer. The compounds in our diet are suggested to play an important role in the aetiology of colon cancer. To investigate the influence of diet on COX-2 in relation to colon cancer cells, a number of human faecal water samples were assessed for their effects on COX-2 enzymatic activity and protein synthesis. Of the faecal waters tested, two samples exhibited a weak inhibitory effect on COX-2 enzymatic activity, and one sample decreased COX-2 protein levels in a colon cancer cell line. The chemical content of faecal water was analysed and a variety of phenolic compounds were identified, including flavonoids and phenolic acids. Hitherto, a number of the identified compounds in faecal water have been assessed for the effects on COX-2, but none of the tested compounds were found to be responsible for the observed effects of faecal water on COX-2. Moreover, the cytotoxic effects of natural COX-2 inhibitors, traditional non-steroidal anti-inflammatory drugs, and the selective COX-2 inhibitor rofecoxib were evaluated using a human cancer cell line panel. Of the compounds tested, curcumin was found to be most potent.This thesis contributes to increase the general knowledge of the effects on COX-2 of commonly occurring plant constituents, including fatty acids and phenolic compounds. As natural parts of our diet, these compounds, abundant in fruits and vegetables, may affect different targets in our bodies, including COX-2.
Source Type:Doctoral Dissertation
Keywords:PHARMACY; Pharmacognosy; Pharmacognosy; Farmakognosi
Date of Publication:01/01/2003