Clin Nutr Res.  2017 Jul;6(3):147-160. 10.7762/cnr.2017.6.3.147.

Chemopreventive and Chemotherapeutic Effects of Fish Oil derived Omega-3 Polyunsaturated Fatty Acids on Colon Carcinogenesis

• Lee JY
• Sim TB
• Lee JE
• Na HK

• KMID: 2385620
• DOI: http://doi.org/10.7762/cnr.2017.6.3.147

Abstract

Colorectal cancer is the third most common cause of cancer related death in the world. Multiple lines of evidence suggest that there is an association between consumption of dietary fat and colon cancer risk. Not only the amount but also the type and the ratio of fatty acids comprising dietary fats consumed have been implicated in the etiology and pathogenesis of colon cancer. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been known to inhibit development of colon cancer by downregulating the expression of genes involved in colon carcinogenesis and also by altering the membrane lipid composition. Data from laboratory, epidemiological, and clinical studies substantiate the beneficial role of n-3 PUFAs in preventing colitis and subsequent development of colon cancer. In addition, recent studies suggest that some n-3 PUFAs can be effective as an adjuvant with chemotherapeutic agents and other natural anticancer compounds in the management of colon cancer. In this review, we discuss chemopreventive and therapeutic effects of fish oil derived long chain n-3 PUFAs, particularly EPA and DHA, with focus on synergetic effects of which they exert when combined with chemotherapeutic agents and other natural compounds.

Keyword

Fatty acids, omega-3; EPA/DHA; Colorectal cancer; Cancer prevention; Therapeutic agent

MeSH Terms

Carcinogenesis*
Colitis
Colon*
Colonic Neoplasms
Colorectal Neoplasms
Dietary Fats
Eicosapentaenoic Acid
Fatty Acids
Fatty Acids, Omega-3
Fatty Acids, Unsaturated*
Fish Oils*
Membranes
Therapeutic Uses
Dietary Fats
Eicosapentaenoic Acid
Fatty Acids
Fatty Acids, Omega-3
Fatty Acids, Unsaturated
Fish Oils
Therapeutic Uses

Figure

• 

  Figure 1 Metabolic formation of EPA and DHA and their conversion to anti-inflammatory and pro-resolving metabolites with chemopreventive and therapeutic potentials. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; n-3, omega-3; ASA, aspirin; COX-2, cyclooxygenase-2; CYP450, cytochrome P450; 18S-HEPE, 18S-hydroxyeicosapentaenoic acid; 18R-HEPE, 18R-hydroxyeicosapentaenoic acid; 18S-RvE1, 18S-resolvin E1; RvE1, resolvins E1; 5-LOX, 5-lipoxygenase; 17S-HDHA, 17S-hydroxy docosahexaenoic acid; 17R-HDHA, 17R-hydroxy docosahexaenoic acid; PD1, protectin D1; RvD1, resolvin D1; 17R-RvD1, 17R-resolvin D1.

• 

  Figure 2 Chemotherapeutic effects of n-3 PUFAs on colon carcinogenesis. n-3, omega-3; PUFAs, polyunsaturated fatty acids; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; n-6, omega-6.

Reference

1. Manzi L, Costantini L, Molinari R, Merendino N. Effect of dietary ω-3 polyunsaturated fatty acid DHA on glycolytic enzymes and warburg phenotypes in cancer. Biomed Res Int. 2015; 2015:137097.

2. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011; 58:2047–2067.

3. Gleissman H, Johnsen JI, Kogner P. Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp Cell Res. 2010; 316:1365–1373.

4. Parada B, Reis F, Cerejo R, Garrido P, Sereno J, Xavier-Cunha M, Neto P, Mota A, Figueiredo A, Teixeira F. Omega-3 fatty acids inhibit tumor growth in a rat model of bladder cancer. Biomed Res Int. 2013; 2013:368178.

5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65:5–29.

6. Xue B, Yang Z, Wang X, Shi H. Omega-3 polyunsaturated fatty acids antagonize macrophage inflammation via activation of AMPK/SIRT1 pathway. PLoS One. 2012; 7:e45990.

7. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009; 22:191–197.

8. Moghaddam AA, Woodward M, Huxley R. Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev. 2007; 16:2533–2547.

9. Chung YW, Han DS, Park YK, Son BK, Paik CH, Lee HL, Jeon YC, Sohn JH. Association of obesity, serum glucose and lipids with the risk of advanced colorectal adenoma and cancer: a case-control study in Korea. Dig Liver Dis. 2006; 38:668–672.

10. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002; 56:365–379.

11. Rao CV, Hirose Y, Indranie C, Reddy BS. Modulation of experimental colon tumorigenesis by types and amounts of dietary fatty acids. Cancer Res. 2001; 61:1927–1933.

12. Byers T. Nutrition and cancer among American Indians and Alaska Natives. Cancer. 1996; 78:1612–1616.

13. Calviello G, Serini S, Piccioni E. n-3 polyunsaturated fatty acids and the prevention of colorectal cancer: molecular mechanisms involved. Curr Med Chem. 2007; 14:3059–3069.

14. Kim IW, Myung SJ, Do MY, Ryu YM, Kim MJ, Do EJ, Park S, Yoon SM, Ye BD, Byeon JS, Yang SK, Kim JH. Western-style diets induce macrophage infiltration and contribute to colitis-associated carcinogenesis. J Gastroenterol Hepatol. 2010; 25:1785–1794.

15. Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther. 1999; 83:217–244.

16. Sarotra P, Kansal S, Sandhir R, Agnihotri N. Chemopreventive effect of different ratios of fish oil and corn oil on prognostic markers, DNA damage and cell cycle in colon carcinogenesis. Eur J Cancer Prev. 2012; 21:147–154.

17. Kang JX, Wang J, Wu L, Kang ZB. Transgenic mice: Fat-1 mice convert n-6 to n-3 fatty acids. Nature. 2004; 427:504.

18. Gravaghi C, La Perle KM, Ogrodwski P, Kang JX, Quimby F, Lipkin M, Lamprecht SA. Cox-2 expression, PGE₂ and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice. J Nutr Biochem. 2011; 22:360–365.

19. Yum HW, Kang JX, Hahm KB, Surh YJ. Constitutive ω-3 fatty acid production in fat-1 transgenic mice and docosahexaenoic acid administration to wild type mice protect against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Biochem Biophys Res Commun. 2017; 487:847–855.

20. Jia Q, Lupton JR, Smith R, Weeks BR, Callaway E, Davidson LA, Kim W, Fan YY, Yang P, Newman RA, Kang JX, McMurray DN, Chapkin RS. Reduced colitis-associated colon cancer in Fat-1 (n-3 fatty acid desaturase) transgenic mice. Cancer Res. 2008; 68:3985–3991.

21. Pike LJ. Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta. 2005; 1746:260–273.

22. Ma DW, Seo J, Switzer KC, Fan YY, McMurray DN, Lupton JR, Chapkin RS. n-3 PUFA and membrane microdomains: a new frontier in bioactive lipid research. J Nutr Biochem. 2004; 15:700–706.

23. Lee EJ, Yun UJ, Koo KH, Sung JY, Shim J, Ye SK, Hong KM, Kim YN. Down-regulation of lipid raft-associated onco-proteins via cholesterol-dependent lipid raft internalization in docosahexaenoic acid-induced apoptosis. Biochim Biophys Acta. 2014; 1841:190–203.

24. Gelsomino G, Corsetto PA, Campia I, Montorfano G, Kopecka J, Castella B, Gazzano E, Ghigo D, Rizzo AM, Riganti C. Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition. Mol Cancer. 2013; 12:137.

25. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008; 233:674–688.

26. Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva C, Senin U, Guralnik JM. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. 2006; 91:439–446.

27. Pradelli L, Mayer K, Muscaritoli M, Heller AR. n-3 fatty acid-enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis. Crit Care. 2012; 16:R184.

28. Zhao J, Dong JN, Wang HG, Zhao M, Sun J, Zhu WM, Zuo LG, Gong JF, Li Y, Gu LL, Li N, Li JS. Docosahexaenoic acid attenuated experimental chronic colitis in interleukin 10-deficient mice by enhancing autophagy through inhibition of the mtor pathway. JPEN J Parenter Enteral Nutr. Forthcoming. 2015.

29. Volkova E, Willis JA, Wells JE, Robinson BA, Dachs GU, Currie MJ. Association of angiopoietin-2, C-reactive protein and markers of obesity and insulin resistance with survival outcome in colorectal cancer. Br J Cancer. 2011; 104:51–59.

30. Surmi BK, Hasty AH. Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Future Lipidol. 2008; 3:545–556.

31. Wagner M, Samdal Steinskog ES, Wiig H. Adipose tissue macrophages: the inflammatory link between obesity and cancer? Expert Opin Ther Targets. 2015; 19:527–538.

32. Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, Shipp LR, Lee J, Walton RG, Adu A, Erfani R, Campbell M, McGehee RE Jr, Peterson CA, Kern PA. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013; 62:1709–1717.

33. Yum HW, Na HK, Surh YJ. Anti-inflammatory effects of docosahexaenoic acid: implications for its cancer chemopreventive potential. Semin Cancer Biol. 2016; 40-41:141–159.

34. Lee HN, Na HK, Surh YJ. Resolution of inflammation as a novel chemopreventive strategy. Semin Immunopathol. 2013; 35:151–161.

35. Titos E, Clària J. Omega-3-derived mediators counteract obesity-induced adipose tissue inflammation. Prostaglandins Other Lipid Mediat. 2013; 107:77–84.

36. Polus A, Zapala B, Razny U, Gielicz A, Kiec-Wilk B, Malczewska-Malec M, Sanak M, Childs CE, Calder PC, Dembinska-Kiec A. Omega-3 fatty acid supplementation influences the whole blood transcriptome in women with obesity, associated with pro-resolving lipid mediator production. Biochim Biophys Acta. 2016; 1861:1746–1755.

37. Zahradka P, Neumann S, Aukema HM, Taylor CG. Adipocyte lipid storage and adipokine production are modulated by lipoxygenase-derived oxylipins generated from 18-carbon fatty acids. Int J Biochem Cell Biol. 2017; 88:23–30.

38. Janakiram NB, Rao CV. Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer. Curr Mol Med. 2009; 9:565–579.

39. Jordan A, Stein J. Effect of an omega-3 fatty acid containing lipid emulsion alone and in combination with 5-fluorouracil (5-FU) on growth of the colon cancer cell line Caco-2. Eur J Nutr. 2003; 42:324–331.

40. Chen XX, Leung GP, Zhang ZJ, Xiao JB, Lao LX, Feng F, Mak JC, Wang Y, Sze SC, Zhang KY. Proanthocyanidins from Uncaria rhynchophylla induced apoptosis in MDA-MB-231 breast cancer cells while enhancing cytotoxic effects of 5-fluorouracil. Food Chem Toxicol. 2017; 107:248–260.

41. Rani I, Vaiphei K, Agnihotri N. Supplementation of fish oil augments efficacy and attenuates toxicity of 5-fluorouracil in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium-induced colon carcinogenesis. Cancer Chemother Pharmacol. 2014; 74:309–322.

42. Calviello G, Di Nicuolo F, Serini S, Piccioni E, Boninsegna A, Maggiano N, Ranelletti FO, Palozza P. Docosahexaenoic acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil. Cancer Chemother Pharmacol. 2005; 55:12–20.

43. Swamy MV, Cooma I, Patlolla JM, Simi B, Reddy BS, Rao CV. Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid: novel strategies for colon cancer prevention and treatment. Mol Cancer Ther. 2004; 3:215–221.

44. Vasudevan A, Yu Y, Banerjee S, Woods J, Farhana L, Rajendra SG, Patel A, Dyson G, Levi E, Maddipati KR, Majumdar AP, Nangia-Makker P. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer. Cancer Prev Res (Phila). 2014; 7:1138–1148.

45. Rao CV, Wang CQ, Simi B, Rodriguez JG, Cooma I, El-Bayoumy K, Reddy BS. Chemoprevention of colon cancer by a glutathione conjugate of 1,4-phenylenebis(methylene)selenocyanate, a novel organoselenium compound with low toxicity. Cancer Res. 2001; 61:3647–3652.

46. Narayanan BA, Narayanan NK, Desai D, Pittman B, Reddy BS. Effects of a combination of docosahexaenoic acid and 1,4-phenylene bis(methylene) selenocyanate on cyclooxygenase 2, inducible nitric oxide synthase and β-catenin pathways in colon cancer cells. Carcinogenesis. 2004; 25:2443–2449.

47. Gullett NP, Ruhul Amin AR, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O. Cancer prevention with natural compounds. Semin Oncol. 2010; 37:258–281.

48. Meyer JL, Gunasekera SP, Scott RM, Paul VJ, Teplitski M. Microbiome shifts and the inhibition of quorum sensing by Black Band Disease cyanobacteria. ISME J. 2016; 10:1204–1216.

49. Kolar SS, Barhoumi R, Lupton JR, Chapkin RS. Docosahexaenoic acid and butyrate synergistically induce colonocyte apoptosis by enhancing mitochondrial Ca²⁺ accumulation. Cancer Res. 2007; 67:5561–5568.

50. Cho Y, Turner ND, Davidson LA, Chapkin RS, Carroll RJ, Lupton JR. Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med (Maywood). 2014; 239:302–310.

51. Hong MY, Bancroft LK, Turner ND, Davidson LA, Murphy ME, Carroll RJ, Chapkin RS, Lupton JR. Fish oil decreases oxidative DNA damage by enhancing apoptosis in rat colon. Nutr Cancer. 2005; 52:166–175.

52. Hong MY, Turner ND, Murphy ME, Carroll RJ, Chapkin RS, Lupton JR. In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27^Kip1 by dietary fish oil and butyrate in rats. Cancer Prev Res (Phila). 2015; 8:1076–1083.

53. Shehzad A, Lee J, Lee YS. Curcumin in various cancers. Biofactors. 2013; 39:56–68.

54. Park W, Amin AR, Chen ZG, Shin DM. New perspectives of curcumin in cancer prevention. Cancer Prev Res (Phila). 2013; 6:387–400.

55. Koeberle A, Northoff H, Werz O. Curcumin blocks prostaglandin E₂ biosynthesis through direct inhibition of the microsomal prostaglandin E₂ synthase-1. Mol Cancer Ther. 2009; 8:2348–2355.

56. Jia Q, Ivanov I, Zlatev ZZ, Alaniz RC, Weeks BR, Callaway ES, Goldsby JS, Davidson LA, Fan YY, Zhou L, Lupton JR, McMurray DN, Chapkin RS. Dietary fish oil and curcumin combine to modulate colonic cytokinetics and gene expression in dextran sodium sulphate-treated mice. Br J Nutr. 2011; 106:519–529.

57. Yin S, Bai H, Jing D. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients: a systemic review and meta-analysis. Diagn Pathol. 2014; 9:91.

58. Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, Dan HC, Boulware D, Cheng JQ, Coppola D. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl- x_L pathway. Cancer Res. 2003; 63:7708–7716.

59. Fenton JI, McCaskey SJ. Curcumin and docosahexaenoic acid block insulin-induced colon carcinoma cell proliferation. Prostaglandins Leukot Essent Fatty Acids. 2013; 88:219–226.

60. Ranelletti FO, Maggiano N, Serra FG, Ricci R, Larocca LM, Lanza P, Scambia G, Fattorossi A, Capelli A, Piantelli M. Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int J Cancer. 2000; 85:438–445.

61. Camuesco D, Comalada M, Concha A, Nieto A, Sierra S, Xaus J, Zarzuelo A, Gálvez J. Intestinal anti-inflammatory activity of combined quercitrin and dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, in rats with DSS-induced colitis. Clin Nutr. 2006; 25:466–476.

62. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002; 2:862–871.

63. Moldawer LL, Copeland EM 3rd. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer. 1997; 79:1828–1839.

64. Sorensen LS, Rasmussen HH, Aardestrup IV, Thorlacius-Ussing O, Lindorff-Larsen K, Schmidt EB, Calder PC. Rapid incorporation of ω-3 fatty acids into colonic tissue after oral supplementation in patients with colorectal cancer: a randomized, placebo-controlled intervention trial. JPEN J Parenter Enteral Nutr. 2014; 38:617–624.

65. Purasiri P, Murray A, Richardson S, Heys SD, Horrobin D, Eremin O. Modulation of cytokine production in vivo by dietary essential fatty acids in patients with colorectal cancer. Clin Sci (Lond). 1994; 87:711–717.

66. Stehr SN, Heller AR. Omega-3 fatty acid effects on biochemical indices following cancer surgery. Clin Chim Acta. 2006; 373:1–8.

67. Tisdale MJ. Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia. Nutrition. 1996; 12:S31–3.

68. Tisdale MJ, Dhesi JK. Inhibition of weight loss by omega-3 fatty acids in an experimental cachexia model. Cancer Res. 1990; 50:5022–5026.

69. Barber MD, Fearon KC, Tisdale MJ, McMillan DC, Ross JA. Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutr Cancer. 2001; 40:118–124.

70. Colomer R, Moreno-Nogueira JM, García-Luna PP, García-Peris P, García-de-Lorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. N-3 fatty acids, cancer and cachexia: a systematic review of the literature. Br J Nutr. 2007; 97:823–831.

71. Guéraud F, Taché S, Steghens JP, Milkovic L, Borovic-Sunjic S, Zarkovic N, Gaultier E, Naud N, Héliès-Toussaint C, Pierre F, Priymenko N. Dietary polyunsaturated fatty acids and heme iron induce oxidative stress biomarkers and a cancer promoting environment in the colon of rats. Free Radic Biol Med. 2015; 83:192–200.

72. Chen CC, Ho CY, Chaung HC, Tain YL, Hsieh CS, Kuo FY, Yang CY, Huang LT. Fish omega-3 fatty acids induce liver fibrosis in the treatment of bile duct-ligated rats. Dig Dis Sci. 2013; 58:440–447.

73. Liang B, Wang S, Ye YJ, Yang XD, Wang YL, Qu J, Xie QW, Yin MJ. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol. 2008; 14:2434–2439.

74. Silva JA, Trindade EB, Fabre ME, Menegotto VM, Gevaerd S, Buss ZS, Frode TS. Fish oil supplement alters markers of inflammatory and nutritional status in colorectal cancer patients. Nutr Cancer. 2012; 64:267–273.

75. Sorensen LS, Thorlacius-Ussing O, Rasmussen HH, Lundbye-Christensen S, Calder PC, Lindorff-Larsen K, Schmidt EB. Effects of perioperative supplementation with omega-3 fatty acids on leukotriene B₄ and leukotriene B₅ production by stimulated neutrophils in patients with colorectal cancer: a randomized, placebo-controlled intervention trial. Nutrients. 2014; 6:4043–4057.

76. Mocellin MC, Pastore e Silva JA, Camargo CQ, Fabre ME, Gevaerd S, Naliwaiko K, Moreno YM, Nunes EA, Trindade EB. Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma fatty acid profile in colorectal cancer patients. Lipids. 2013; 48:879–888.

77. Gee JM, Watson M, Matthew JA, Rhodes M, Speakman CJ, Stebbings WS, Johnson IT. Consumption of fish oil leads to prompt incorporation of eicosapentaenoic acid into colonic mucosa of patients prior to surgery for colorectal cancer, but has no detectable effect on epithelial cytokinetics. J Nutr. 1999; 129:1862–1865.

78. Trabal J, Leyes P, Forga M, Maurel J. Potential usefulness of an EPA-enriched nutritional supplement on chemotherapy tolerability in cancer patients without overt malnutrition. Nutr Hosp. 2010; 25:736–740.

79. Tokudome S, Kuriki K, Yokoyama Y, Sasaki M, Joh T, Kamiya T, Cheng J, Ogawa K, Shirai T, Imaeda N, Goto C, Tokudome Y, Ichikawa H, Okuyama H. Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: a randomized controlled trial in polypectomized participants. Prostaglandins Leukot Essent Fatty Acids. 2015; 94:1–11.

80. Kuan CY, Walker TH, Luo PG, Chen CF. Long-chain polyunsaturated fatty acids promote paclitaxel cytotoxicity via inhibition of the MDR1 gene in the human colon cancer Caco-2 cell line. J Am Coll Nutr. 2011; 30:265–273.

81. Granci V, Cai F, Lecumberri E, Clerc A, Dupertuis YM, Pichard C. Colon cancer cell chemosensitisation by fish oil emulsion involves apoptotic mitochondria pathway. Br J Nutr. 2013; 109:1188–1195.

82. Ma H, Das T, Pereira S, Yang Z, Zhao M, Mukerji P, Hoffman RM. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model. Anticancer Res. 2009; 29:2421–2426.

83. Camuesco D, Gálvez J, Nieto A, Comalada M, Rodríguez-Cabezas ME, Concha A, Xaus J, Zarzuelo A. Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, attenuates colonic inflammation in rats with DSS-induced colitis. J Nutr. 2005; 135:687–694.