Resveratrol for a Healthier Prostate

Resveratrol Inhibits
Prostate Cancer

In cancer-prone mice, it arrests the disease early on
and prevents its progression to the advanced stage
By Will Block

hen Rodgers and Hart wrote “This Lady Is a Tramp” for the Broadway musical Babes in Arms in 1937, they were spoofing the pretentious rules of etiquette of New York’s high society types. With elegant wit, they turned logic on its head and made a “tramp” into an appealing character (because she was, of course, not really a tramp at all). True tramps—from garden-variety bad girls to the current generation of pop culture bimbos who become rich and famous for their sluttish behavior—give womanhood a bad name.

Manhood, on the other hand, doesn’t get a bad name from male tramps, because they’re just vagrants, not “sluts.” It’s so unfair! This article is about a topic intimately associated with manhood: the prostate gland, the source of a man’s seminal fluid—and a mouse’s seminal fluid, for that matter. Tiny though it be, a mouse’s prostate is just as important to him as ours is to us, even if the mouse doesn’t know it.

This Mouse Is a TRAMP

Pity, then, the poor little mouse that medical scientists call a TRAMP. It stands for transgenic adenocarcinoma of the mouse prostate, a mouthful meaning a mouse that has been genetically engineered to be highly susceptible to spontaneously developing prostate cancer (the prefix adeno- means glandular), in a manner that closely mimics prostate cancer in humans. TRAMP mice figure prominently in a study carried out recently by researchers at the University of Alabama at Birmingham.1

They wanted to know whether resveratrol, the fabled health and longevity compound found in grapes and red wine, might offer protection against prostate cancer. Since genetically engineering humans to make them susceptible to cancer is widely frowned upon, the researchers had to settle for the furry little rodents and hope that their findings would shed some light on the human condition.

Prostate Cancer—Slow but Deadly

The human condition, in a nutshell, is this: prostate cancer is second only to lung cancer as a cause of death in American men. According to the American Cancer Society, the year 2007 will see an estimated 218,890 new cases of prostate cancer in the United States, and the disease will kill about 27,050 of its victims.2

Although prostate cancer is primarily a disease of older men, it can strike middle-aged men too, and it actually gets a toehold early in the life of most men, in the form of prostatic intraepithelial neoplasias (PIN), which is medical jargon for precancerous lesions in the inner lining (the epithelium) of the prostate gland. It has been estimated that the incidence of low-grade PIN is 9%, 16%, and 26% in men aged 20, 30, and 40, respectively.3 In another study, the same group of researchers estimated that the frequency of high-grade PIN—the precursor to prostate adenocarcinoma—is 0%, 5%, 10%, 41%, and 63% in men in their 20s, 30s, 40s, 50s, and 60s, respectively.4

Get the picture? If you’re a man and you live long enough, you will almost certainly get prostate cancer, according to the experts. It’s not a matter of if, but when. Of course, the kind of prostate cancer you get will play a key role in what kind of treatment, if any, you should receive. “If any” sounds callous, doesn’t it? But if a man is old enough and his cancer is sufficiently slow in progressing (most prostate cancers are slow), he may be statistically likely to outlive the cancer and die of something else. In such cases, “watchful waiting” on the cancer is often deemed preferable to therapy that may cause more grief and expense than it’s worth.

For Prevention, Choose Resveratrol

But enough about statistics and therapy. What we all want is prevention, a word that should perhaps be tattooed on the foreheads of physicians (in mirror printing, so they could read it in the bathroom every morning). By prevention, we really mean risk reduction, and that is what the Alabama researchers set out to measure, using male TRAMP mice that were fed powdered resveratrol mixed into their daily chow.

The researchers chose resveratrol (pronounced rez·VEER·ah·troll) because of its known ability, in laboratory studies, to reduce the risk of heart disease, cancer, diabetes, and neurodegenerative diseases. These benefits have been ascribed in part to resveratrol’s apparent antioxidant and anti-inflammatory properties, but its biological activity extends far beyond those arenas, into complex domains of gene regulation and the modulation of various cell-signaling pathways.*


*For a selection of prior articles on resveratrol, see “Resveratrol and Quercetin—Puzzling Gifts of Nature” (July 2005), “Resveratrol Prolongs Life in a Vertebrate!” (April 2006), “Resveratrol—Star Molecule Against Disease and Aging” (August 2006), “Revolutionary Antiaging Discovery with Resveratrol” (January 2007), and “Resveratrol Boosts Energy Metabolism” (August 2007).


Two Mechanisms of Interest

Among the mechanisms of resveratrol’s actions are two in which the researchers were particularly interested because of the compound’s potential, in their view, to protect the prostate gland. Although previous studies had shown that dietary resveratrol can suppress chemically induced mammary tumors (breast cancer) in rodents, there had been no animal studies on the use of resveratrol for preventing prostate cancer.

One of the mechanisms of interest is regulation of the expression of the prostate cells’ receptor molecules for sex hormones, both male (androgens) and female (estrogens), all of which are steroids. (In molecular biology, expression means any detectable effect of a gene. The primary function of most genes is to encode the information necessary for the cellular synthesis of a protein—in this case, one of the receptors for sex hormones. Whether one speaks of expressing the gene or expressing the protein, it implies the same thing: production of the protein.)

The other mechanism of interest is modulation of the signaling pathway instigated by insulinlike growth factor-I (IGF-I), a protein hormone that plays a key role in regulating the rate of cellular division and growth throughout the body. (A signaling pathway is a cascade of chemical reactions that carry information from the outer membrane of a cell to the cell’s nucleus, in response to an outside stimulus, such as the presence of a hormone. The process begins when the hormone binds to its receptor molecule on the cell surface.)

Caution—Drunken Mice?

Starting when the TRAMP mice were 5 weeks old, the researchers gave them 625 mg of resveratrol per kg of their diet, i.e., the diet contained 0.0625% resveratrol by weight (this dose was extrapolated from the results of one of the breast cancer studies). The control mice received the same diet without resveratrol. Since an adult mouse eats about 5 g of food per day, the test mice consumed about 3 mg of resveratrol per day, or the equivalent of about 3 bottles of red wine per day (imagine how drunk those little TRAMPs would be!).*


*The amount of resveratrol in red wine varies greatly, from near zero to a few milligrams per liter, and the average amount in a standard 750-mL bottle is about 1 mg. And since one bottle contains five 150-mL (5-oz) glasses, one such glass contains, on average, about 0.2 mg (200 mcg) of resveratrol.


In terms of dry weight, a human eats about 50 times as much as a mouse (about 250 g per day), so if our food contained that same concentration of resveratrol, we would ingest about 150 mg of resveratrol per day, or the equivalent of about 150 bottles of red wine. In reality, of course, our food contains very little resveratrol (there are small amounts in grapes, peanuts, and mulberries), but it’s easy to obtain substantial amounts through supplementation.

An 87% Drop in Advanced Prostate Cancer

Resveratrol was well tolerated by the TRAMP mice, with no signs of toxicity or changes in food or water intake, body weight, or individual tissue weights, compared with the controls. Some of the mice were killed at 12 weeks of age for studies of the mechanism of resveratrol’s actions, and the rest were killed at 28 weeks of age to determine resveratrol’s chemopreventive effect on their prostate cancer.

The effect was dramatic: the incidence of advanced prostate cancer dropped from 23% in the controls to only 3% in the resveratrol-treated mice. That’s an 87% drop (23 – 3 = 20, and 20/23 = 0.87). This is not to say, however, that most of the resveratrol-treated mice did not develop prostate cancer—in fact, most of them did (remember that these little TRAMPs were designed to get it). But, whereas 42% of the controls had early-stage cancer when they were killed (and 23% had advanced cancer), 62% of the resveratrol-treated mice had early-stage cancer (and only 3% had advanced cancer). What this means is that resveratrol effectively halted most cancers at the early stage, preventing them from progressing to the advanced stage. That, obviously, buys a mouse (or a man) time.

“. . . a huge impact on human lives”

Not surprisingly, the researchers also observed a marked decrease (by 43%) in cell proliferation, the process by which cancers grow. They commented, “In our study, the reduction in proliferation most likely plays a major factor in the chemopreventive action of resveratrol.”

There were substantial increases in the expression of some of the sex hormone receptors in prostate tissue, but there were no changes in the serum concentrations of the major sex hormones. The ramifications of these findings are too complicated to go into here, as are those of the researchers’ findings regarding various changes in the IGF-I signaling pathway.

The authors stated,1

To our knowledge, this is the first study to show that resveratrol in the diet suppresses spontaneously developing prostate cancer in an animal model. . . . The ability to delay the onset or diminish the progress of slowly developing cancers, such as prostate cancer, by chemoprevention can have a huge impact on human lives. . . . Although we may not wipe out prostate cancer, we do hope to suppress the progression of prostate cancer so men can extend their lives and quality of life. Supporting our chemoprevention finding is [sic] the mechanistic data that resveratrol can regulate cell proliferation, sex steroid receptor protein expression, and specific growth factor signaling proteins in the prostate.

Toward Better Health for Mice and Men

An interesting aspect of the study arose from the fact that mouse prostate glands consist of three lobes, the two most important of which were examined separately in the study. The researchers found that resveratrol’s mechanisms of action in these two lobes were substantially different, in ways that complicated the interpretation of their results. Pointing out that human prostate glands consist of three “zones” that are analogous, in principle, to the rodent glands’ three lobes, they stated,

It is fundamentally important to differentiate between the actions of resveratrol in both lobes of the rodent. Future work should determine the similarities and differences in biochemistry between rodent prostate “lobes” and human prostate “zones” in order to correctly correlate animal studies with the clinical manifestations of human prostate cancer.

In other words, it may be even more difficult than usual to extrapolate with confidence from animals to humans in studies such as this. But considering the abundance of evidence, from laboratory and animal studies, that resveratrol can provide anticancer benefits, along with anti-heart disease benefits—not to mention its proven ability to extend the maximum lifespan of a variety of creatures—it would be foolish not to avail oneself of everything it may offer in terms of improved human health, including a reduced risk for prostate cancer.

Well done, you little TRAMPs.

References

  1. Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA, Lamartiniere CA. Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis, Advance Access, published online Aug 3, 2007. doi:10.1093/carcin/bgm144.
  2. Cancer Facts & Figures 2007. American Cancer Society, Atlanta, GA, 2006. See www.cancer.org.
  3. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993;150:379-85.
  4. Sakr WA, Ward C, Grignon DJ, Haas GP. Epidemiology and molecular biology of early prostatic neoplasia. Mol Urol 2000;4:109-13; discussion, 115.

Muscadine Skin Extract Fights Cancer Too

If you’re from the southeastern United States, you’re surely familiar with muscadines. Less fortunate Americans may not know that a muscadine is a large, thick-skinned grape from which delicious juice, jellies, jams, preserves, syrups, and dessert toppings are made—and sweet wines too. The muscadine (Vitis rotundifolia) is America’s original native grape, many varietals of which are now cultivated in the Southeast. Muscadines are often called scuppernongs, although that name properly belongs to a particular bronze-colored muscadine varietal. (Some other varietals are red or purple, but most are almost black.)

Scientists have become interested in muscadines because they contain more resveratrol than grapes of the species Vitis vinifera, from which almost all wines, worldwide, are made.1 As in all other grapes, the resveratrol in muscadines is concentrated in the skin and seeds (in muscadines, most of it is in the skins), with relatively little in the pulp. And, as in all other grapes, the actual amount varies greatly, depending on numerous factors. Unless the resveratrol content of a given batch of grapes or wine is measured, there’s no way of knowing how much (if any) they contain.

Recently, a group of researchers from several American government and academic institutions collaborated on a study of the effects on prostate cancer of a muscadine skin extract containing no significant amount of resveratrol at all.2 Does that make sense? Yes, because grape skins do, after all, contain innumerable other compounds besides resveratrol, and it would be useful to investigate their health benefits too. For example, dark-colored grape skins are rich in anthocyanins, a type of flavonoid known to have anticancer and other health benefits.

In their study, the researchers used several human prostate cancer epithelial cell lines representing different stages of progression of the disease, as well as normal prostate epithelial cells. They investigated both the resveratrol-free muscadine skin extract and resveratrol side by side so they could compare and contrast the effects and mechanisms of action of the two agents. Oddly, they did not include a muscadine seed extract in these experiments, even though they cited prior evidence that such an extract also has anticancer activity. They did establish, however, that the chemical compositions—and hence, presumably, the biological activities—of the skin extract and the seed extract are markedly different.

Also markedly different, despite some areas of overlap, were both the effects and the mechanisms of action of resveratrol and the muscadine skin extract (MSE). The details are too complex to discuss here, but we can summarize the main findings:

  • Both resveratrol and MSE altered the structure and inhibited the growth (by different mechanisms) of prostate cancer cells, but not of normal prostate cells. This suggests that neither of these agents is likely to have toxic effects (and both are, in fact, considered to be nontoxic).

  • Resveratrol inhibited the proliferation of prostate cancer cells by interfering with the cell cycle, the process by which a cell divides and becomes two cells.

  • MSE preferentially inhibited the proliferation of prostate cancer cells by inducing apoptosis, or programmed cell death (resveratrol did not do this). The fact that all the cancer cell lines, representing different stages of the disease, responded to MSE in this manner suggests that the active compounds may inhibit cancer at its earliest stages.

The researchers were able to show, furthermore, that the activity of MSE could be attributed, at least in part, to fractions of the extract that did not contain compounds with known anticancer effects, such as ellagic acid, gallic acid, and quercetin. Other compounds with anticancer activity must, therefore, also have been present. The likeliest candidates for such activity are anthocyanins. (These plant pigments give many vegetables, fruits, and berries their characteristic colors—in this case, colors so dark that most of the muscadine varietals appear black.)

A group of anthocyanins that has attracted particular interest in another area of medicine has the self-descriptive name purple corn color. In one study, this pigment has been shown to prevent weight gain in mice that were on a high-fat diet. By preventing obesity, it can help prevent insulin resistance and type 2 diabetes. (See “Purple Corn Color May Help Prevent Obesity” in the June 2007 issue.)

References

  1. Ector BJ, Magee JB, Hegwood CP, Coign MJ. Resveratrol concentration in muscadine berries, juice, pomace, purees, seeds, and wines. Am J Enol Vitic 1996;47:57-62.
  2. Hudson TS, Hartle DK, Hursting SD, Nunez NP, Wang TTY, Young HA, Arany P, Green JE. Inhibition of prostate cancer growth by muscadine grape skin extract and resveratrol through distinct mechanisms. Cancer Res 2007;67(17):8396-405.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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