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Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808
2To whom correspondence should be addressed. E-mail: hardmawe{at}pbrc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • (n-3) fatty acids • cancer • nutrition • alternative cancer therapy
Using animal models, researchers have repeatedly shown that the growth of chemically induced cancers and of human cancer xenografts can be slowed or completely inhibited by incorporation of (n-3) fatty acids in the diet [examples: (1–5)]. There are a few articles indicating that (n-3) fatty acids may be beneficial for human cancer therapy [examples: (6,7)]. The objective of this article is to briefly review the evidence for the effects of (n-3) fatty acids on cancer growth or cancer therapy, and to highlight rational mechanisms for those effects. Knowledge in this field is rapidly expanding as a result of new molecular biology techniques that allow the identification of novel mechanisms for the actions of fatty acids and increased interest in nontoxic alternative therapies for cancer.
What are (n-3) fatty acids?
Fatty acids are hydrocarbon chains with a carboxyl group at the head (
) end and a methyl group at the tail (n) end (Fig. 1). The carbons may be connected by single or double bonds. The number of carbons in the chain and the type of bond between the carbons give rise to the different types of fatty acids. The bonds between all carbons in saturated fatty acids are fully saturated with hydrogen and are single bonds. Monounsaturated fatty acids and PUFA have bonds that are not saturated with hydrogen, thus one or more double bonds connect the carbons. The first double bond in an (n-6) fatty acid is 6 carbons from the n end; the first double bond in an (n-3) fatty acid is 3 carbons from the n end. Mammals, including humans, can synthesize saturated fatty acids and monounsaturated (n-9) fatty acids but cannot synthesize either the (n-6) or the (n-3) double bond. The (n-3) and (n-6) fatty acids are essential components in cell membrane phospholipids and as a substrate for various enzymes; thus, fatty acids containing these bonds are essential fatty acids (EFA)3 and must be obtained in the diet. The (n-6) fatty acid is consumed primarily as linoleic acid [abbreviated as 18:2(n-6), meaning 18 carbons, 2 double bonds, (n-6) type] from vegetable oils but some arachidonic acid [AA; 20:4(n-6)] is also obtained from meats (8). The (n-3) fatty acids may be consumed as 
-linolenic acid [18:3(n-3)], which is contained in various amounts in some oils [canola (11%), 18:3(n-3); flaxseed (57%); soybean (8%)] and in leafy green vegetables. Longer-chain (n-3) fatty acids, mainly EPA [20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)], are found in fish and fish oils. The (n-3) and (n-6) fatty acids cannot be interconverted, but both can be elongated and desaturated to form other fatty acids of the same series (9). Humans have the enzymes to elongate 18:3(n-3) to EPA and DHA, but it is not clear how important this pathway is in humans. Certainly the best source of EPA and DHA is from fish or fish oils in the diet. The production of AA from linoleic acid by the 
-5 and -6 desaturases is suppressed by -linolenic acid, EPA, and DHA, the 3 major (n-3) fatty acids (10).
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COX has 2 isozymes: COX 1 and COX 2. COX 1 is constitutively produced by most cell types, and COX 2 is produced as part of the inflammatory response. Incorporation of (n-3) fatty acids has been shown to suppress the production of COX 2 (11,12) and can reduce the inflammatory response (13) by changing the types of eicosanoids that are produced. Because inflammation has been associated with cancer promotion, the use of COX inhibitors to reduce inflammation has shown promise as a cancer preventive strategy (14–16).
Effects of (n-3) fatty acids on cancer
Supplementing the diet of tumor-bearing mice or rats with oils containing EPA or DHA has slowed the growth of various types of cancers, including lung (17,18), colon (19,20), mammary (21–23), and prostate (24). The (n-3) fatty acids have been shown to increase the efficacy of various cancer chemotherapy drugs and of radiation therapy against cancer. For example, the efficacies of doxorubin, (17,25,26), epirubicin (27), 5-fluorouracil (28), mitomycin C (29), arabinosylcytosine (30), tamoxifen (31), and CPT-11 (22,28), and of radiation therapy (32) have been enhanced when long-chain (n-3) fatty acids were included in the diet of rodents or culture medium of cells being treated.
Another potential benefit of (n-3) fatty acids supplementation is the effect of these fats on cachexia. Cachexia is the wasting away of lean mass that is not corrected by increasing energy consumption. Pancreatic cancer patients often develop debilitating cachexia. Some have shown weight gain and improved quality of life after daily supplementation of the diet with an energy- and protein-dense (610 kcal, 32.2 g protein) liquid supplement containing 2.2 g EPA and 0.96 g DHA (33). Patients who consumed the supplement that contained energy and protein but that did not contain the (n-3) fatty acids did not gain weight.
Why are (n-3) fatty acids effective against cancer?
Many mechanisms have been proposed for suppression of tumor cell growth by (n-3) fatty acids, and new mechanisms are frequently reported as we gain additional knowledge of the regulation of gene expression by fatty acids. It is likely that suppression of tumor cell growth by (n-3) fatty acids is due to the combination of these mechanisms rather than to a single, unique activity that is the sole mechanism of action. Some of the mechanisms proposed for the action of (n-3) fatty acids against cancer are as follows.
If (n-3) fatty acids are available, they will be used as a substrate by COX 2. It has been reported that DHA inhibits eicosanoid synthesis from AA (34), EPA is a better substrate for COX than AA (35), and EPA competes more successfully than AA for COX activity (13,35). The result is that if (n-3) fatty acids are included in the diet and are incorporated into cell membranes, then less of the inflammation-producing and growth-promoting prostaglandin E2 will be produced in normal and in tumor tissues.
Residual and metastatic tumor cells must multiply for the tumor to recur or for metastatic cells to grow into a life-threatening tumor. AA promotes growth by activating protein kinase C to stimulate mitosis (36); (n-3) fatty acids do not. The (n-3) fatty acids decrease activation of oncogenic transcription factors ras and AP1 (37,38), which are transcription factors for many growth-promoting genes. The AA-derived products of COX and LOX stimulate mitosis, whereas the EPA-derived products of COX and LOX decrease cancer growth (39,40). Thus (n-3) fatty acids can slow growth of cancer cells by direct action and by their activity as second messengers.
When activated, the transcription factor, nuclear factor 
B (NFB), blocks programmed cell death or apoptosis (41). NFB is often upregulated in cancer cells, resulting in cells that are resistant to chemotherapy drugs or radiation and do not die in response to the genetic damage that has occurred. The Bcl-2 family of genes and COX 2 expression can also block apoptosis, resulting in cells that do not die at the appropriate time. The (n-3) fatty acids can restore functional apoptosis by downregulating NFB (41), which in turn downregulates COX 2 expression (42,43), and by downregulating the expression of Bcl-2 family genes (44,45).
The (n-3) fatty acids have been shown to induce differentiation of breast cancer cells (46). Terminally differentiated cells do not multiply, so induction of differentiation could stop the growth of tumors.
As cancers grow, new blood vessels must develop to supply nutrients to the cells and to remove wastes. Inhibition of angiogenesis has been proposed as a strategy to inhibit or to limit tumor growth. The (n-3) fatty acids inhibit angiogenesis by multiple mechanisms, including alterations in prostaglandin production and inhibition of protein kinase C (42,47–50).
Many early breast cancers are estrogen dependent. Prostaglandin E2, a product of AA, activates P450 aromatase and increases the production of estrogen (51). The (n-3) fatty acids could decrease the growth of estrogen-dependent breast cancers by decreasing estrogen stimulation of these tumors.
In summary, multiple mechanisms can play a role in suppression of tumor growth by (n-3) fatty acids. Some of the mechanisms may play a more dominant role in particular tumor types (i.e., alteration of estrogen is likely to be more important for suppression of breast cancer than for esophageal cancer). However, the proposed mechanisms are not mutually exclusive, and it is likely that multiple mechanisms contribute to suppression of cancer growth.
Feasibility of use in human cancer treatment
The results of animal studies are quite promising that (n-3) fatty acids may be a clinically useful addition to cancer therapy. However, a very high level of (n-3) supplement was used in many of the animal studies, often 20–24% (by weight) of the diet. These results may be a useful proof of concept, but it is also important to know how much (n-3) fat can be consumed by humans and whether this amount can effectively suppresses cancer growth.
Burns et al. (52) reported the results of a phase 1 (dose tolerance) trial using an (n-3) supplement showing that the maximum tolerated dose of this supplement was 0.3 g/kg per day or up to 21 g/d for a 70-kg patient (52). Twenty-one capsules contained 13.1 g of EPA plus DHA per day. A number of reports from the group of K. C. Fearon, M. J. Tisdale, S. J. Wigmore, M. D. Barber et al. cite the effects of (n-3) fatty acid supplements on weight loss in pancreatic cancer patients. Early studies (53) used as much as 12 g fish oil (18% EPA/12% DHA) per day and found that weight loss was ameliorated and that the patients actually began to gain weight. The results of a later study indicated that 2.2 g/d of EPA + 0.96 g DHA contained in a protein- and energy-dense supplement would ameliorate weight loss and improve the quality of life of pancreatic cancer patients significantly better than the supplement without EPA (33). This group has also reported the effects of the nutritional supplement on metabolic mediators in pancreatic cancer patients (7). In this study, serum IL-6 and excreted proteolysis-inducing factor were significantly reduced in the group that consumed EPA. The results of a study on the effects of EPA with or without megestrol acetate indicated that EPA increased appetite and weight gain in patients with cancer-associated wasting (54), but the increase was not any better than the increase due to megestrol. The patients in the later study consumed 2.18 g/d of EPA. Information gained from the 2 studies indicates that an effective dose of EPA to reduce cachexia may be between 2 and 4 g/d. These data indicate that humans can consume enough (n-3) fatty acids to influence cytokine production and that only small amounts of (n-3) may be required to significantly influence cell cytokines.
A report by Bougnoux et al. (55) presents some evidence that (n-3) fatty acids may be useful during human cancer therapy. These results indicate that the level of DHA in breast adipose tissue of patients with complete or partial remission in response to cytotoxic drugs was higher than in patients with no response or progression. This higher level represented increased long-term consumption of (n-3) fatty acids by these patients. It is also possible to increase DHA in breast tissue by short-term (3 mo) consumption of (n-3) fatty acids (56). Even though scant in number, these reports provide encouraging evidence that (n-3) fatty acids may be beneficial for cancer therapy in humans.
In conclusion, preclinical studies indicate that (n-3) fatty acids should be beneficial for cancer treatment. Mechanistic studies indicate feasible mechanisms for the influence of (n-3) fatty acids on tumor growth, survival, and response to chemotherapy. A limited number of clinical studies indicate that (n-3) fatty acids may be beneficial when consumed before chemotherapy. It seems important to commence human trials using an (n-3) fatty acid as a supplement to standard chemotherapy.
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FOOTNOTES |
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3 Abbreviations used: AA, arachidonic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LOX, lipoxygenase; NFB, nuclear factor B.
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