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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 INTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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B activation and bcl-2 expression, thus allowing apoptosis of cancer cells; and 5) reducing cancer-induced cachexia. It seems reasonable to assume that after appropriate cancer therapy, consumption of omega-3 fatty acids might slow or stop the growth of metastatic cancer cells, increase longevity of cancer patients and improve their quality of life.
KEY WORDS: • cancer • cancer survival • omega-3 fatty acids • nutrition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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–6
). Epidemiologic studies indicate that populations that consume high amounts of omega-3 (n-3) fatty acids have lower incidences of breast, prostate and colon cancers than do those that consume less n-3 fatty acids. Many of the mechanisms that are thought to slow or prevent the growth of cancers may also be postulated to slow or prevent the growth of metastatic or residual cancer cells. Thus increasing the consumption of n-3 fatty acids may be a nontoxic way to augment cancer therapy and to significantly increase life span. This summary is not intended to be a complete review of all the mechanisms of action of n-3 fatty acids but will highlight some of the important actions of n-3 fatty acids to inhibit cancer cell growth. |
Background |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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). Because humans cannot desaturate the n-3 or the n-6 bond, both n-3 and n-6 fatty acids are essential fatty acids (EFAs)3
that must be obtained from dietary sources. Most n-6 fatty acid is consumed as linoleic acid (LA) [18 carbons, two double bonds, n-6 or 18:2(n-6)] primarily from vegetable oils, especially corn, safflower and soybean oils, and meat, but some arachidonic acid (AA) [20:4(n-6)] is also obtained from meats (7
). n-3 fatty acids may be found in vegetable oils, especially canola and soybean oil, and green leafy vegetables as 
-linolenic acid (LNA) [18:3(n-3)] and in larger amounts in fatty cold-water fish as eicosapentaenoic acid (EPA) [20:5(n-3)] or docosahexaenoic acid (DHA) [22:6n-3]. Both n-3 and n-6 fatty acids may be incorporated into cell membrane phospholipids as consumed in the diet or may be elongated and desaturated to longer-chain fatty acids of the same series (8
), but n-3 and n-6 fatty acids cannot be interconverted. The same enzymes use both n-3 and n-6 fatty acids as substrate for subsequent production of various cytokines. All three major n-3 fatty acids—LNA, EPA and DHA—suppress the production of AA from LA by competing more successfully than LA for the activity of the 
5 and 6 desaturases (9
).
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), hepatocellular (11
), cervical (12
) and pancreatic (13
) cancer; squamous carcinoma of the esophagus (14
); bladder transitional cell carcinoma (15
); colon cancer (16
); and breast cancer (17
,18
). There is interest in the use of COX-2–specific inhibitors as a strategy for cancer prevention and in combination with cancer chemotherapy (19
–22
). |
How might n-3 fatty acids improve survival of cancer victims? |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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Changes in eicosanoid metabolism.
n-3 fatty acids can inhibit the induction of COX-2 (23
,24
). Figure 2
illustrates the suppression of COX-2 in MDA-MB 231 human breast cancer xenografts in nude mice with n-3 fatty acids in their diet. COX inhibitors have been used to suppress the growth of colon cancers (25
,26
), demonstrating that suppression of COX-2 may be a useful strategy to slow growth of metastatic tumors.
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). Thus n-3 fatty acids may be beneficial by reducing production of COX-2 and by changing the type of product produced by COX-2.
However, there is also evidence that n-3 fatty acids suppress COX-2 expression by inhibiting nuclear factor-B (NF-B) (Fig. 3
). NF-B is the transcription factor that induces the expression of inflammatory response cytokines, including interleukins-1 and-6, COX-2 and tumor necrosis factor and of growth factors such as interleukin-2 and granulocyte colony stimulating factor (28
). Constitutive activation of NF-B in cancers seems to play a role in tumor growth and cancer cell survival (28
). Interleukins-1 and-6 and tumor necrosis factor may play a role in the cachexia associated with many cancers (29
,30
). Thus suppression of the activation of NF-B by n-3 fatty acids not only reduces the production of proproliferative eicosanoids produced by COX-2 but also suppresses the production of other NF-B–induced cytokines that promote cancer cell growth and that may be detrimental to the cancer victim.
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Cancer cells must multiply for a tumor or metastatic site to grow. At least three mechanisms have been identified by which n-3 fatty acids suppress mitosis. LA and AA activate protein kinase C (31
) and induce mitosis but EPA and DHA appear to reverse the protein kinase C activity changes associated with colon carcinogenesis (32
,33
). n-3 fatty acids decrease the activity of ras (34
) and AP-1 (35
) oncogenes that are frequently activated in cancers and that stimulate mitosis. The AA products of COX and LOX increase mitosis; EPA and DHA decrease mitosis and inhibit growth of breast and colon cancers (36
–39
).
Restoring functional apoptotic pathways to help control cancer growth.
Apoptosis is programmed cell death. When apoptotic pathways are functional, cells with unreparable genetic damage should die. However, apoptotic pathways are frequently disrupted in cancers. Increased COX-2 expression alone has been shown to block apoptosis (40
). In addition, NF-B is frequently activated in cancer cells and NF-B activation has been shown to block apoptosis (28
). Thus blocking of NF-B and COX-2 activation by n-3 fatty acids would be expected to contribute to restoration of apoptosis. When activated, genes of the Bcl-2 family can block apoptosis. DHA has been reported to inactivate Bcl-2 family genes and increase transcription of genes and transcription factors that induce apoptosis (41
,42
).
Induction of differentiation.
Terminally differentiated cells do not multiply. n-3 fatty acids have been shown to induce differentiation of breast cancer cells (43
).
Suppression of angiogenesis.
Angiogenesis, the growth of new blood vessels, must occur for cancers to grow. The n-6 products of COX and LOX stimulate angiogenesis; the n-3 products of COX and LOX do not stimulate angiogenesis (33
,44
,45
).
Altering estrogen metabolism.
The promotion of breast cancer by estrogen is well known. Perhaps less well known is that prostate and colon cancers also exhibit estrogen receptors and that the growth of prostate and colon cancers can be promoted by estrogen (46
,47
). Prostaglandin (PG)E2, an AA product, activates P450 aromatase, increasing estrogen production (48
). PGE3, an EPA product, does not activate P450 aromatase. Thus a decrease in PGE2 and an increase in PGE3 would be expected to decrease estrogen production and decrease stimulation of cell growth. A shift in estrogen metabolism toward 16-hydroxylation increased the formation of aberrant hyperproliferation in mammary explant cultures (49
). In a clinical study, an n-3 dietary supplement decreased 16-hydroxylation (50
) in human breast tissue and would be expected to decrease hyperproliferation in breast tissues.
In summary, the results of experimental studies show that n-3 fatty acids may be detrimental to the growth of metastatic or residual cancer cells by altering eicosanoid metabolism, slowing cancer cell mitosis, increasing cancer cell death, inducing differentiation, suppressing angiogenesis and altering estrogen metabolism. Numerous animal studies illustrate that incorporating n-3 fatty acids into the diet of mice suppressed the growth of chemically induced cancers or implanted human xenografts (36
,51
–63
)., Figure 4
illustrates the 75% suppression of the tumor growth rate seen when an n-3 fatty acid supplement was incorporated in the diet of mice bearing an MDA-MB 231 human breast cancer xenograft.
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Reduction of cancer risk by consumption of n-3 fatty acids |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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,55
,58
,61
,64
,65
,66
). Breast cancer incidence in Japanese women increases within one generation after migration to the United States (66
). The incidence of breast, prostate and colon cancers is increasing in Japan (67
) and in Alaskan natives (66
) as the cultures adopt a Western diet, decrease fish intake and increase dietary intake of n-6 fatty acids.
Both animal and epidemiologic studies indicate that the ratio of n-3 to n-6 fatty acids in the diet is particularly important to the reduction of cancer risk. In animal studies the ratio of 1.2:1 has reduced cancer incidence (68
). n-3 consumption was not significantly correlated to cancer incidence, but the ratio of n-3 to n-6 fatty acids in the diet was significantly inversely correlated to breast cancer incidence in three of four European countries examined in one study (69
) and in France (70
). In the French study, the odds ratio for breast cancer in the quartile with the highest ratio of n-3 to n-6 fatty acids consumed was 0.3 compared with an odds ratio of 1 for the quartile with the lowest the ratio of n-3 to n-6 fatty acids (70
). Because these are epidemiologic studies there is no way to tell whether the reduced risk for cancer was due to reduced cell transformation or to death of the transformed cells before an overt cancer developed.
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Dietary reduction of cancer risk |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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) and with diets that appear to reduce risk for cancer. Because the ratio of n-3 to n-6 fatty acids in the diet affects the competitive advantage of n-3 fatty acids, it seems logical that n-6 fatty acid consumption should be reduced and that consumption of n-3 fats should be increased. As recommended by the American Institute for Cancer Research and by the U.S. Department of Agriculture, our diets should incorporate less meat and include more fruits, vegetables and whole grains to reduce total fat consumption. Such a change would also increase the beneficial antioxidants and phytochemicals contained in the fruits and vegetables.
To incorporate more heart-healthy fats in their diet, Americans have decreased their use of saturated fatty acids and have in large part substituted safflower, corn and soybean oils for frying and baking uses. These oils contain a very high amount of n-6 fatty acid (LA) and very little n-3 fatty acid (LNA) (Fig. 5
). The use of canola or olive oil instead of safflower, corn or soybean oil for frying and baking would reduce the consumption of n-6 fatty acids. In addition, canola oil includes a significant amount of n-3 fatty acids. Consumption of one or more servings per week of fatty, cold-water fish and perhaps an n-3 supplement would add significant n-3 fatty acids to the diet.
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FOOTNOTES |
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3 Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid; LNA, linolenic acid; LOX, lipoxygenase; NF-B, nuclear factor-B; PG, prostaglandin.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONBackgroundHow might n-3 fatty...Reduction of cancer risk...Dietary reduction of cancer...LITERATURE CITED |
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63% n-3 fatty acids.
