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The role of cyclooxygenase in n-6 and n-3 polyunsaturated fatty acid mediated effects on cell proliferation, PGE2 synthesis and cytotoxicity in human colorectal carcinoma cell lines

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Author: Dommels, Y.E.M. · Haring, M.M.G. · Keestra, N.G.M. · Alink, G.M. · Bladeren, P.J. van · Ommen, B. van
Type:article
Date:2003
Source:Carcinogenesis, 3, 24, 385-392
Identifier: 236977
doi: doi:10.1093/carcin/24.3.385
Keywords: Biology · Analytical research · 5 (4 fluorophenyl) 1 [(4 methylsulfonyl)phenyl] 3 trifluoromethylpyrazole · 5,8,11,14,17 icosapentaenoic acid · acetylsalicylic acid · alpha tocopherol · antioxidant · arachidonic acid · ascorbic acid · carbene · celecoxib · cyclooxygenase 2 inhibitor · docosahexaenoic acid · indometacin · interleukin 1beta · linoleic acid · malonaldehyde · nonsteroid antiinflammatory agent · omega 3 fatty acid · omega 6 fatty acid · prostaglandin E2 · prostaglandin synthase · antineoplastic activity · cancer cell · cell growth · cell proliferation · colon cancer · colorectal carcinoma · controlled study · cytotoxicity · drug effect · drug mechanism · enzyme activation · enzyme activity · fatty acid synthesis · growth inhibition · human · human cell · hypothesis · incubation time · lipid peroxidation · priority journal · review · signal transduction · Antioxidants · Caco-2 Cells · Cell Division · Colorectal Neoplasms · Cyclooxygenase Inhibitors · Dinoprostone · Fatty Acids, Omega-3 · Fatty Acids, Omega-6 · Fatty Acids, Unsaturated · HT29 Cells · Humans · Lipid Peroxidation · Prostaglandin-Endoperoxide Synthases

Abstract

This study was conducted to investigate the role of the enzyme cyclooxygenase (COX) and its prostaglandin product PGE2 in n-6 and n-3 polyunsaturated fatty acid (PUFA)-mediated effects on cellular proliferation of two human colorectal carcinoma cell lines. The long chain PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and arachidonic acid (AA; 20:4n-6) both inhibited cell proliferation of Caco-2 cells compared with the long chain fatty acids α-linolenic acid (ALA; 18:3n-3) and linoleic acid (LA; 18:2n-6). Neither incubation with PGE2 nor reduction in PGE2 synthesis by EPA compared with AA led to differential effects on cell proliferation in Caco-2 cells. This suggests that n-6 and n-3 PUFA-mediated cell proliferation in Caco-2 cells is not regulated via PGE2 levels. AA and EPA had no effect on growth of HT-29 colon cancer cells with a low COX activity. However, stimulation of COX-2 activity by IL-1β resulted in a decrease in cell proliferation and an induction of cytotoxicity by AA as well as by EPA. Both inhibition of the COX pathway by indomethacin as well as inhibition of direct lipid peroxidation by antioxidants such as vitamin E and C diminished the anti-proliferative effects of AA as well as EPA. Also, malondialdehyde, a product of lipid peroxidation and COX-activity was decreased by addition of vitamin E and partially decreased by indomethacin. These data support the hypothesis that growth inhibitory and cytotoxic effects of PUFAs with methylene-interrupted double bonds such as AA and EPA are due to peroxidation products that are generated during lipid peroxidation and COX activity. Chemicals/CAS: 5 (4 fluorophenyl) 1 [(4 methylsulfonyl)phenyl] 3 trifluoromethylpyrazole, 162054-19-5; 5,8,11,14,17 icosapentaenoic acid, 10417-94-4, 1553-41-9; acetylsalicylic acid, 493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; ascorbic acid, 134-03-2, 15421-15-5, 50-81-7; carbene, 2465-56-7; celecoxib, 169590-42-5; docosahexaenoic acid, 25167-62-8, 32839-18-2; indometacin, 53-86-1, 74252-25-8, 7681-54-1; linoleic acid, 1509-85-9, 2197-37-7, 60-33-3, 822-17-3; malonaldehyde, 542-78-9; prostaglandin E2, 363-24-6; prostaglandin synthase, 39391-18-9, 59763-19-8, 9055-65-6; Antioxidants; Cyclooxygenase Inhibitors; Dinoprostone, 363-24-6; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Prostaglandin-Endoperoxide Synthases, EC 1.14.99.1