A Growing Arsenal Against Cancer

Cancer is the second leading cause of death in the U.S., exceeded only by heart disease. The American Cancer Society (ACS) estimates that about 555,500 Americans are expected to die of cancer this year, more than 1,500 people a day.

About 16 million new cancer cases have been diagnosed since 1990, and about 1,284,900 new cancer cases are expected to be diagnosed in 2002. Prostate cancer in males and breast cancer in females rank the highest among new cancer cases in 2002. They are also the second leading types of cancer that cause death in both sexes (Table 1).

Between 30% and 40% of all cases of cancer are preventable by feasible and appropriate diets and by physical activity and maintenance of appropriate body weight, according to the American Institute for Cancer Research (AICR). On a global basis and at current rates, this means that appropriate diets may prevent 3–4 million cases of cancer every year. AICR is the only major American cancer organization focusing exclusively on diet, nutrition, and cancer and was the first organization to promote dietary guidelines to reduce the risk of cancer. AICR’s diet and health guidelines for cancer prevention include:
1. Choose a diet rich in a variety of plant-based foods.

2. Eat plenty of vegetables and fruits.

3. Maintain a healthy weight and be physically active.

4. Drink alcohol only in moderation, if at all.

5. Select foods low in fat and salt.

6. Prepare and store food safely.

“It is the whole diet that makes a difference in cancer prevention,” stressed Melanie Polk, AICR’s Director of Nutrition Education. By following these guidelines, she said, consumers can get phytochemicals from fruits, vegetables, and grains thought to prevent cancer. “All of these food components can play a protective role in a healthful diet.”

Antioxidants
Antioxidants in fruits and vegetables are one of the contributing factors to cancer prevention. According to AICR, diets containing substantial and varied amounts of vegetables and fruits will prevent as much as 20% or more of all cases of cancer. Antioxidants function by donating electrons to free radicals and neutralizing them. This prevents cell destruction in the body. The following antioxidants have been linked to cancer prevention:
• Vitamin A (retinol) is available in foods in two ways: preformed from animal food sources and derived from beta-carotene in plant foods. Dietary sources include liver, fortified milk, carrots, spinach, and sweet potatoes. The body requires vitamin A to maintain healthful tissues.

• Beta-carotene is one of the more controversial carotenoids. A proform of vitamin A, it is present in vegetables and fruits. In three major clinical trials, people were given high doses of synthetic beta-carotene in an attempt to prevent lung cancer and other cancers. Two studies found beta-carotene supplements to be associated with a higher risk of lung cancer in cigarette smokers, and a third found neither benefit nor harm from beta-carotene supplements. ACS recommends that smokers are better off avoiding beta-carotene supplements.

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• Vitamin C is found in many fruits and vegetables, including citrus fruits, strawberries, green peppers, and broccoli. It acts as a reducing agent and can reduce the formation of carcinogenic nitrosamines in the stomach, minimize destruction of vitamin A, and also keep the folate coenzymes intact to prevent their destruction. Many studies have linked consumption of foods rich in vitamin C to a reduced risk for cancer.

• Vitamin E is found in whole grains, vegetable oil, and green leafy vegetables. It helps protect red blood cells and minimize lipid destruction by free radicals.

New research shows that vitamin E could inhibit the development of prostate cancer. In one clinical trial reported in the May 28, 2002, Proceedings of the National Academy of Sciences, men who took 50 mg of vitamin E per day had a lower risk of prostate cancer than men who took a placebo.

Researchers from the University of Rochester carried out experiments on the alpha-tocopheryl succinate form of vitamin E. They found that the vitamin suppressed the production of a receptor for testosterone, the androgen receptor (AR), which is a marker of the cancer’s development. They reported that by lowering the number of ARs in a prostate cancer cell, the genes that stimulate cancer growth are less likely to be activated. They also observed that vitamin E was able to inhibit the growth of the prostate cancer cells.

The authors hope that their research could lead to new therapies in preventing and treating prostate cancer. They suggested that vitamin E supplements could be added to other AR-inhibiting methods to destroy the potential for prostate cancer cell growth, and that vitamin E might work best when consumed with other natural treatments that also have promising results against prostate cancer, such as vitamin D and selenium.

• Lycopene is a red carotenoid found in tomatoes, watermelon, pink grapefruit, and guava. It is more readily available in cooked tomatoes, especially tomatoes cooked with a little bit of fat, Polk said.

Most of the ongoing research has looked at the relationship between lycopene and the reduced risk of prostate cancer. Interest in lycopene developed after Edward Giovannucci of the Harvard School of Public Health reported in 1995 that regular intake of tomato sauces lowered the risk of prostate cancer by 45%.

• Selenium is a mineral, as well as an antioxidant, that the body needs as part of its defense mechanisms. It is a cofactor for the activity of the enzyme glutathione peroxidase, which metabolizes peroxides into less-toxic alcohols and water. Animal studies suggest that selenium protects against cancer, but repeated and well-controlled studies are needed to confirm these observations. Dietary sources for selenium include tuna, beef, white bread, and chicken.

Grape Extracts
Resveratrol is an antioxidant found largely in the skin of red grapes. Fresh grape skin contains about 50–100 μg/g. Researchers in the College of Pharmacy at the University of Illinois–Chicago reported in Science in 1997 that resveratrol was effective during all three phases of the cancer process: initiation, promotion, and progression.

Resveratrol exhibited antioxidant and antimutagenic activity and also increased levels of the Phase II drug-metabolizing enzyme quinone reductase, which is capable of metabolically detoxifying carcinogens, thereby ridding them from the body. Resveratrol also demonstrated antiinflammatory effects and inhibited the activity of the cyclooxygenase and hydroperoxidase enzymes (suggestive of antipromotion activity), in addition to causing the differentiation of human promyelocytic leukemia cells, indicating that this compound may also depress the progression phase of cancer. Finally, resveratrol inhibited the development of preneoplastic lesions in mouse mammary glands treated with a carcinogen in culture and inhibited tumor formation in mice.

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Recent research has also identified a new compound from grapes with similar cancer-fighting properties. Agnes Rimando, research chemist at the U.S. Dept. of Agriculture’s Agricultural Research Service (ARS), discovered a compound called pterostilbene, which possesses similar cancer chemopreventive qualities to those found in resveratrol. It also showed strong inhibitory activity against breast cancer cell lines. The study, prompted by pterostilbene’s close structural similarity to resveratrol, was conducted with the use of a mouse mammary gland culture model that was exposed to a chemical carcinogen. The carcinogen caused precancerous cells on which the compound was tested. Rimando stressed that the evidence remained preliminary and that the compound had yet to be evaluated in humans.

Green Tea
Green tea is rich in flavonoids, which are powerful antioxidants. Research from both the National Foundation for Cancer Research and the University of Kansas reported that green tea is 100 times more potent than vitamin C and 25 times more potent than vitamin E at protecting cells from damage linked to cancer, heart disease, and other illnesses. Most of the data supporting the anticancer benefits of tea at this point are derived from animal studies in which animals were treated with amounts of polyphenols equivalent to amounts consumed by regular tea drinkers. Evidence is the strongest for prevention of cancers of the oral cavity, stomach, and colon.

When any carcinogen enters the body, it must often be activated by Phase I enzymes, explained Linda Quattrochi, Assistant Professor at the University of Colorado Health Sciences Center, at AICR’s 2001 Research Conference. A widely cited example of this system involves hydrocarbons, which can enter the body via charred meat. Under normal circumstances, hydrocarbons bind to a specific receptor that causes Phase I enzymes to be “switched on.” The enzymes transform hydrocarbons into larger, more-reactive (more-water-soluble) carcinogenic compounds that are easier for the body to dispose of. Occasionally, however, Phase I enzymes generate products that are considerably toxic and carcinogenic themselves.

When certain dietary components are present—such as certain flavonoids found in tea—they bind to precisely the same receptor that hydrocarbons do. As a result, the flavonoid compounds change the way the enzymes are put together so dramatically that the enzymes cannot do their job. When this happens, fewer carcinogens are produced.

Quattrochi and her colleagues reasoned that if one kind of flavonoid binds with one kind of receptor, other flavonoids are likely to bind with other receptors to inhibit Phase I enzymes and other “cancer-promoting” systems. She has found that many different flavonoids found in such foods as oranges, horseradish, mustard, turmeric, and both green and chamomile teas can inhibit a wide variety of cancer-promoting reactions.

Broccoli
Almost a decade ago, Paul Talalay, Professor at Johns Hopkins University, successfully isolated sulforaphane, a natural antioxidant compound that arises when broccoli (and other cruciferous vegetables) is cooked, chopped, or chewed. In repeated experiments, it has been associated with a potent ability to induce the family of Phase II detoxification enzymes without affecting the Phase I enzymes.

At AICR’s 2001 Research Conference, Talalay discussed evidence indicating that the family of compounds known as isothiocyanates (including broccoli’s sulforaphane) also function as indirect antioxidants. “The distinction between the actions of direct antioxidants and indirect antioxidants is key,” he said. “Direct antioxidants like vitamin C, vitamin E, and beta-carotene wage a one-on-one war against potentially dangerous substances known as ‘free radicals,’ which arise as a byproduct of normal metabolism. Direct antioxidants bind directly to free radicals before these compounds can inflict the kind of genetic damage that leads to cancer.”

Indirect antioxidants cannot and do not bind directly to free radicals, he explained. Instead, they use a variety of means to boost the overall antioxidant capacity of cells. According to Talalay’s research, sulforaphane acts as an indirect antioxidant by “turning on” a wide variety of Phase II enzymes that serve to protect the cell from genetic damage. Because sulforaphane is capable of inducing so many different Phase II enzymes, which in turn defend against many different kinds of damage, it affords the cell a more varied and efficient form of protection than can be provided by single, direct antioxidants.

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Talalay has also found that the overall protection provided by sulforaphane and other Phase II inducers persists for a longer time. Perhaps most important, he said, is that because the overall antioxidant protection afforded by Phase II inducers is indirect, they are unlikely to enter directly into oxidative reactions and exhibit “pro-oxidant” behavior.

The cancer-preventing health properties of sulforaphane found in broccoli are available in a new consumer product being test marketed. Brassica Protection Products, Baltimore, Md., is marketing Brassica® Teas in green tea, green tea with lemon, green tea with orange, and decaffeinated versions. The black teas with sulforaphane, trademarked as SGS, include Chinese Sencha black tea and decaffeinated black tea. Each cup of Brassica tea provides 15 mg of SGS, the same amount as an average 3-oz serving of adult broccoli. The SGS is naturally extracted with water from broccoli seeds, then added to the teas as a dried powder. Once market tests are complete in Denver, the brand will roll out to supermarkets, and health, vitamin, and gourmet stores across the United States.

Flaxseed
Flaxseed provides essential nutrients, including protein, essential fatty acids, vitamins, and minerals. “There is some evidence that flaxseed can be protective against prostate cancer, but the research is very young,” Polk said. “There is also some promising research about potential benefits of flaxseed and breast cancer risk.” It is one of the richest sources of lignans, a type of phytoestrogen, which may help protect against cancer, particularly hormone-sensitive cancers such as those of the breast and prostate.

Flaxseed contains healthy amounts of both soluble and insoluble fiber. The soluble fiber can help lower cholesterol, and the insoluble fiber aids in digestion by increasing bulk. The added bulk reduces the amount of time that waste remains in the body and prevents constipation, characteristics that may help protect against colon cancer.

Flaxseed also contains alpha-linoleic acid, an essential omega-3 fatty acid. Omega-3 fatty acids not only help lower the risk of cardiovascular disease and stroke, but also play a beneficial role in infant development and inflammatory disorders.

Polk cautioned that until more research is conducted, people undergoing breast cancer treatment and pregnant women should avoid flaxseed because it has estrogenic effects. Those taking the drug tamoxifen should also avoid flaxseed.

Soy Isoflavones
Soy contains several phytochemicals, some of which have weak estrogen activity and appear to protect against hormone-dependent cancers in animal studies. Epidemiological and experimental evidence suggests that consumption of soy-based foods is associated with a decreased risk of cancer. These anticancer effects are thought to be related to the high isoflavone content in soy.

Researchers at Ohio State University evaluated the isoflavone content of a soyrich bread to determine the effects of its major ingredients (soy milk powder and soy flour) on the proliferation of a human prostate cancer cell line, PC-3. They extracted isoflavones from soy flour and soy milk powder and determined the isoflavone concentration and composition in the extracts. Soy-rich bread extracts contained 353.8 μg of total isoflavones/g, of which 38% was found in daidzein form, 55% in genistein form, and 6% in glycitein form after enzymatic hydrolysis. Soy flour and soy milk powder extracts contained 1,711.1 μg and 1,549.6 μg of total isoflavones/g, respectively. PC-3 cells were treated with growth medium containing varying concentrations (0–3.3 mg/mL) of the soy flour and soy milk powder isoflavone extracts for 24 hr, and cellular proliferation was assessed.

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Extracts (3.3 mg/mL) of soy flour and soy milk powder decreased proliferation of PC-3 cells by 12.8% and 10.4%, respectively, compared to controls receiving no extract. Both soy flour and soy milk powder extracts inhibited PC-3 cell proliferation. There was a positive association between the concentration of isoflavones present in the extracts and a decrease in cell proliferation. These observations support the hypothesis that soy ingredients with different isoflavone profiles can inhibit prostate cancer cell growth to different extents.

AICR is funding several studies looking at the relationship between soy and cancer. Lee-Jane Lu at the University of Texas Medical Branch is studying whether both the amount and type (soy vs animal) of dietary protein may determine hormone levels and thus influence breast cancer risk. Alison Duncan at the University of Guelph is currently determining whether there is any relationship between soy isoflavones in the diet and hormone levels in healthy young men. And Gertaud Maskarinec at the University of Hawaii is examining soy foods, isoflavones, insulin-like growth factor I, and breast cancer risk.

Calcium
Calcium is not just associated with preventing osteoporosis, Polk stated. “There appear to be some protective aspects in terms of cancer, most recently in regard to colon cancer.”

Several studies have suggested that foods high in calcium might help reduce the risk of colorectal cancer and that supplementing the diet with calcium modestly reduces the formation of colorectal adenomas (polyps). However, there is also evidence that a high-calcium intake, primarily through supplements, is associated with increased risk for prostate cancer, especially for prostate cancers that are more aggressive. In light of this, ACS recommends that both men and women should strive to consume recommended levels of calcium, primarily through food sources. Recommended intake levels of calcium are 1,000 mg/day for people ages 19–50 years and 1,200 mg/day for people over 50.

Vitamin D
New studies by researchers at the Howard Hughes Medical Institute indicate that vitamin D protects against colon cancer by helping to detoxify cancer-triggering chemicals that are released during the digestion of high-fat foods.

The discovery, which was made by a team of researchers that included David J. Mangelsdorf at the University of Texas Southwestern Medical Center, Ronald M. Evans of The Salk Institute, and colleagues at the University of Arizona, was reported in the May 17, 2002, issue of Science. The studies show that a specific type of bile acid, called lithocholic acid (LCA), a known carcinogen, activates the vitamin D receptor. When the receptor is switched on, it triggers other proteins that detoxify the bile acid.

The research suggests that a drug that acts like vitamin D might help in preventing colon cancer by turning on the vitamin D receptor and clearing LCA from the  body. One obstacle that must be overcome, however, is that high intake of vitamin D or drugs that mimic vitamin D can lead to dangerous levels of calcium in the blood.

“There’s an abundance of epidemiologic data, as well as some scientific data, suggesting a correlation between high-fat diets, bile acids such as LCA, and colon cancer,” Mangelsdorf said. “But there has been no causal link, which has been one of the frustrating aspects of trying to understand the relationship between our Western-style high-fat diet and colon cancer.”

Although it had been shown that vitamin D can prevent colon cancer in rats treated with LCA and that humans with defective vitamin D signaling pathways have a higher incidence of colon cancer, it remained unclear how vitamin D actually prevents colon cancer. A reasonable theory, Mangelsdorf said, was that vitamin D and LCA both triggered a biochemical pathway involved in detoxifying LCA. The best candidate was a pathway that involved the vitamin D receptor.

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According to Mangelsdorf, the findings suggest that the vitamin D receptor acts as a sensor for the toxic chemical LCA. Other receptors in the body can sense dietary fats and other foreign chemicals and serve to “alert” the body to begin detoxification when the chemicals reach dangerous levels.

“Our findings suggest a new look at the relationship between nutrition and cancer, particularly how vitamin D protects against colon cancer,” he said. “One problem with using vitamin D as a protective drug has always been that it produces hypercalcemia. But now we know that there’s another endogenous compound, LCA, that can also attach to the receptor. This suggests that we can develop protective drugs that don’t produce hypercalcemia, but do activate the detoxification pathway.”

Conjugated Linoleic Acid
Conjugated linoleic acid (CLA) is a collective term used to describe one or more positional and geometric isomers of linoleic acid, an essential fatty acid. The majority of in-vitro and experimental animal studies of CLA and cancer support CLA’s effectiveness in reducing risk of this disease. By far, most investigations of CLA and cancer have focused on mammary cancer, according to the National Dairy Council.

In a series of studies reported by the National Dairy Council, researchers demonstrated that CLA inhibits chemically induced rat mammary tumors at various stages of carcinogenesis, regardless of the amount or type of dietary fat and independently of linoleic acid. CLA inhibited cancer in a dose-dependent manner at levels of 1% and below, with no further beneficial effect at levels above 1%. When dietary CLA was fed to laboratory animals at 0.05, 0.1, 0.25, and 0.5% by weight, as little as 0.1% CLA reduced mammary tumors.

In-vitro studies reported in Cancer Letters in 1992 also support the ability of CLA to inhibit the proliferation of human breast cancer cells. When estrogen-responsive human breast cancer cells (MCF-7) were incubated with varying physiological concentrations of CLA for 2–12 days, cell growth was reduced in a dose and time-dependent manner. Moreover, CLA was more effective than beta-carotene in inhibiting cell proliferation. The studies also demonstrated that CLA reduced the growth of other cancer cell lines, including human malignant melanoma, colorectal, liver, and lung adenocarcinoma.

How CLA inhibits carcinogenesis is under investigation. Although CLA’s anticarcinogenic activity was once thought to be due to its antioxidant properties, more recent research disputes this hypothesis. Multiple mechanisms are likely to explain CLA’s anticarcinogenic effect, including its ability to modulate eicosanoid synthesis, increase vitamin A status, and/or enhance the immune response. Further research is needed to elucidate the feasibility of testing CLA in human intervention trials as a cancer-preventive agent.

Whey Protein
Whey products contain a variety of bioactive components. Anticancer properties have been reported for alpha-lactalbumin, lactoferrin, bovine serum albumin, conjugated linoleic acid, sphingolipids, butyric acid, calcium, casein glycomacropeptide, and fat globule membrane proteins. Limited human clinical trials support some of the claimed benefits, but much more work with human subjects is required.

Laboratory animal and in-vitro studies indicate that whey proteins have anticarcinogenic effects. In a study reported in Journal of Nutrition in 1995, fewer chemically induced colon tumors developed in laboratory rats fed whey protein diets than in rats fed experimental diets containing casein, meat, or soy proteins. This effect was attributed to increased tissue concentration of glutathione, which was stimulated by the whey protein diet. However, other mechanisms may be involved.

In another study reported in Journal of Dairy Science in 1997, when alpha-lactalbumin was incubated with two different mammalian intestinal cell lines, cell division decreased, whereas peptides from fermented casein had no effect on cell division. Bovine lactoferrin may also be beneficial in the prevention of some cancers.

Research continues to unveil a growing number of cancer-preventive substances. Consumers, however, should not focus or consume specific supplements for cancer prevention, but should focus on the whole diet, Polk advised. “This area of research is so young, and more human studies need to be conducted,” she said. Learning more about these nutraceuticals such as soy, antioxidants and conjugated linoleic acid helps us understand why the whole fruit, vegetable, soybean, or grain is cancer-preventive.

by LINDA MILO OHR
Contrtibuting Editor
Chicago, Ill.