Ratio of n 6 to n-3 Fatty Acids in the Diet Affects Tumor Growth and Cachexia in Walker 256 Tumor-Bearing Rats

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Author	Pizato, Nathalia Bonatto, Sandro L. Yamazaki, Ricardo Key Aikawa, Júlia Nogata, Cláudia Mund, Rogéria C. Nunes, Everson Araújo Piconcelli, Maressa Naliwaiko, Katya Curi, Rui Calder, Philip C. Fernandes, Luiz Cláudio Maluhy
Copyright Year	2006
Abstract	In this study we investigate the impact of the dietary ratio of n-6 to n-3 fatty acids (FAs) from postweaning until adult age upon tumor growth, lipid peroxidation in tumor tissue, and metabolic indicators of cancer cachexia in Walker 256 tumor-bearing rats. Weanling male Wistar rats received a normal low-fat (40 g/kg diet) chow diet or high-fat diets (300 g/kg) that included fish oil (FO) or sunflower oil or blends of FO and sunflower oil to yield n-6 to n-3 FA ratios of approximately 6:1, 30:1, and 60:1 ad libitum. After 8 wk, half of each group was inoculated with 1 ml of 2 × 107 Walker 256 cells. At the 14th day after tumor inoculation, the animals were killed, and tumors and blood were removed. The different diets did not modify the blood parameters in the absence of tumor bearing, except the high-FO diet, which decreased serum cholesterol and triacylglycerol concentrations. Tumor weight in chow-fed rats was 19 g, and these rats displayed cancer cachexia, characterized by hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, loss of body weight, and food intake reduction. Tumor weight in FO-fed rats was 7.7 g, and these animals gained body weight (14.6 g) and maintained blood metabolic parameters similar to non–tumor-bearing animals. Tumor weight in rats fed the diet with an n-6 to n-3 FA ratio of 6:1 was similar to tumor-bearing, chow-fed rats, but they gained 2 g in the body weight and blood metabolic parameters were similar to those in non–tumor-bearing rats. However, a further increase in the n-6 FA content of the diet did not change the cachectic state associated with tumor bearing. In this experimental model, a dietary n-6 to n-3 FA ratio of 6:1 was able to increase food intake and body weight, restore the biochemical blood parameters of cachexia, and prevent the development of cancer cachexia. Introduction Major changes in the type and amount of fat consumed by humans have occurred over the last 150 yr (1,2). Western societies have been characterized by an increase in the intake of omega-6 (n-6) fatty acids (FAs) and a decrease in the intake of omega-3 (n-3) FAs (2). It is proposed that the balance of n-6 to n-3 FAs in the diet is of importance to human health and disease (2). This may relate to the ability of certain n-6 and n-3 polyunsaturated FAs (PUFA) to be metabolized to form eicosanoids such as prostaglandins (PGs) and leukotrienes (3–6). Eicosanoids produced from the n-6 PUFA arachidonic acid enhance tumor cell proliferation and so are associated with the cancer development (3,7,8). Eicosanoids produced from the n-3 PUFA eicosapentaenoic acid are frequently much less potent (up to 100-fold) than the analogs produced from arachidonic acid (9). Hence, the relative amounts of n-6 and n-3 PUFA provided by the diet, and so present in blood and tissues, may be of importance to the development of some cancers (10–12). Indeed, chemically induced rat mammary carcinogenesis is promoted by dietary n-6 PUFA (13) but is inhibited by feeding n-3 PUFA-rich fish oil (FO) (14). Likewise, experimental rat colon carcinogenesis is inhibited by feeding a diet rich in n-3 PUFA (15–18). Furthermore, growth of human mammary and colon cancer cell lines as solid tumors in athymic (“nude”) mice is inhibited by feeding a diet rich in n-3 PUFA (19,20). These and similar studies indicate the ability of n-3 PUFA to exert protective effects against some common cancers in animal models. Cancer growth is accompanied by cachexia, which occurs in about one-half of untreated cancer patients (21). Cancer NUTRITION AND CANCER, 53(2), 194–201 Copyright © 2005, Lawrence Erlbaum Associates, Inc. N. Pizato, S. Bonatto, R. K. Yamazaki, J. Aikawa, C. Nogata, R. C. Mund, E. A. Nunes, M. Piconcelli, K. Naliwaiko, and L. C. Fernandes are affiliated with the Department of Physiology, Biological Sciences Building, Federal University of Paraná, 81530–970 Curitiba, PR., Brazil. R. Curi is affiliated with the Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil. P. C. Calder is affiliated with the Institute of Human Nutrition, University of Southampton, Southampton, United Kingdom. cachexia is characterized by anorexia, asthenia, anemia, weight loss, weakness, and intense peripheral catabolism with depletionofcarbohydrate, lipid, andprotein stores (21,22).As a result of a multifactorial etiology involving immune-metabolic pathways, the basic mechanisms that induce cancer cachexia are poorly known (22). A number of conditions have been postulated to play a key role in establishing cancer cachexia. These include excess production of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6,and interferon-γ (23), lowplasmalevelsof insulin (24), high plasma levels of glucagon, cortisol, catecholamines,andvasopressin(25),and thepresenceofPGE2 (26). In addition to effects on the production of eicosanoids involved in tumor cell proliferation and tumor growth, n-3 PUFA from FO have been demonstrated to decrease the production of cytokines such as TNF and IL-6 in healthy individuals (27–29) and in patients with pancreatic cancer (30). There are also reports of normalization of the metabolic response in pancreatic cancer–bearing patients supplemented with FO (30–32). These studies indicate that n-3 PUFA from FO might be efficacious in treating cachexia even in advanced stages of cancer. Most previous studies carried out to investigate the effect of dietary FAs on tumor growth in laboratory animals have used young adult animals fed for a short period with a particular diet before or after induction of the tumor. Recently, we provided a dietary regimen of 1 g/kg body weight of FO for one generation that was able to reduce tumor growth and cancer cachexia in Walker 256 tumor-bearing rats (33). In this study, we investigate the impact of the dietary ratio of n-6 to n-3 PUFA from postweaning until adult age upon tumor growth, lipid peroxidation in tumor tissue, and metabolic indicators of cancer cachexia in Walker 256 tumor-bearing rats. Material and Methods Chemicals, Oils, Drugs, and Enzymes Chemicals and enzymes used were obtained from Sigma Chemical Co. (St. Louis, MO). FO was kindly donated by the Herbarium Foundation (Curitiba, Brazil). The FO used was a mixed marine triacylglycerol (TAG) preparation containing 130 g eicosapentaenoic acid and 200 g docosahexaenoic acid per kilogram. Sunflower oil was from BUNGE Alimentos (Ponta Grossa, Brazil) and contained ~60% of linoleic acid, and coconut oil was from Industria Brasileira de Gordura de Coco LTDA (Ponta Grossa, Brazil). The α-tocopherol contents of the oils used to prepare the diets were 11.9 (coconut oil), 19.5 (sunflower oil), and 12.4 (FO) μg/ml.
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