Last month, this column provided an overview for “Thinking About Cancer,” relying on information supplied in a book on prostate cancer that I co-authored several years ago. For those who would like to explore the topic of cancer in greater detail, that book is still available at amazon.com under the title, The Prostate Miracle: New Natural Therapies That Can Save Your Life. As noted in the previous column, researchers giving advice on preventing cancer usually present cancer as developing in three distinct stages: initiation, promotion, and progression. The existence of these stages suggests that there are distinct measures that can be taken to protect against cancer. This month, we will explore some options for preventing initiation and promotion as well as courses of action for those who already are beyond the “prevention” stage and want to be proactive in their own treatment.
The Usual Suspects and What They Do
Cancer does not just pop up out of the blue. Most researchers accept that there is a sequence of events leading to the appearance of a true cancer. The schema includes several steps. In the first step, either a procarcinogen or a carcinogen leads to the initiation of the cancer, that is, the development of the initial genetic damage. The difference? Whereas a carcinogen itself directly initiates the development of the cancer, a procarcinogen requires the action of an activating enzyme from our body before it can initiate cancerous changes. An example of the action of activating enzymes is given below in the context of the discussion of liver enzymes. From initiation, the cancer process must pass through the stages of promotion (such as through the impact of chronic inflammation or infection) and progression before the cancer develops. Following this stage of cancer is metastasis, the spread of the cancer to tissues beyond the original site. Therefore, the stages of cancer development are usually given as initiation, promotion, progression, cancer and metastasis.
Quite a number of factors have been suggested as causes of cancer in general and prostate cancer in particular. For the sake of convenience, these factors broadly can be divided into those that involve oxidation and free radicals and those that involve the failure of the body’s detoxification machinery. In reality, of course, there is an enormous degree of overlap between these two, but the division remains heuristically useful. Aside from the free radical theory and toxicity theories, there are also suggestions that the levels of hormone and of other compounds natural to our bodies can be too elevated or otherwise initiate cancer. Once these ways of looking at procarcinogens and carcinogens have been explained, then more specific elements can be taken up. For instance, if one believes that a high fat diet causes prostate cancer, it remains to be explained whether this is because of the generation of free radicals, an inhibition of detoxification pathways or an inappropriate dysregulation of hormone levels. Therefore, it is worthwhile to begin with the general theories before getting down to specifics.
By far the most widely known factor suggested as a cause of cancer is the action of free radicals. The free radical theory begins by observing that oxygen is a ubiquitous agent in bodily reactions. Glycolysis, the cleaving of carbon bonds from carbohydrate molecules to release energy, creates free radicals. The burning of lipids in anaerobic respiration (cellular energy production in the absence of adequate oxygen) creates free radicals. The functioning of the immune system during phagocytosis (the attack by large white blood cells, like little Pac-men, upon invaders) creates free radicals. The mere presence of many minerals in the body, especially but not limited to iron and copper, provides catalysts that create free radicals (which, in part, is why the ratio of copper to zinc is so important). The immune system’s inflammation response, the most primitive of our immune responses, creates free radicals.
These free radicals are simply atoms and molecules that carry unpaired electrons. In chemistry the term radical refers to a component that can be involved in many reactions in sequence without itself undergoing change. Free radicals typically initiate cascades of free radical formation, with each step creating yet another damaging radical. These radicals attack fats and proteins, damage cell membranes, inactive important cell enzymes and ultimately interfere with the cellular DNA strands. The methylation process is another one of the body’s defenses for its DNA against damage by free radicals.
Free radicals can be scavenged or “put out of action” in many different ways. The simplest procedure is for an antioxidant to donate an electron—it is this electron that puts the free radical out of action—and then itself forms a stable molecule. This second step is important because the molecules which gives up the electron, unless it somehow becomes part of a stable molecule, yields yet another free radical!
The amino acid L-cysteine provides an example of this process: Cysteine donates an electron, becomes cystine, and then two cystine molecules cross link to form a structural protein of use to the body to make collagen. Antioxidants are, by definition, substances that are very easily oxidized and which, when oxidized, become harmless and easily excreted or are actually of some positive benefit to the body. Vitamin C is perhaps the best-known example of these compounds.
Many scavenging processes require several steps. For instance, one type of radical known as the superoxide molecule (O2-) first is turned into the less reactive hydrogen peroxide (H2O2) by the enzyme superoxide dismutase (SOD), and then this hydrogen peroxide is converted to water and plain oxygen by glutathione. Glutathione, in turn, is made more effective in its role in the presence of vitamin C, which can be oxidized and then excreted. Of particular interest with regard to prostate cancer, it is those prostate cells that are glutathione deficient which become cancerous.
Lycopene, the bright red compound found in tomatoes and made more available to the body when tomatoes are cooked with a fat or oil, recently has been widely publicized as a reason that Italian men have relatively low levels of prostate cancer. Lycopene is a powerful antioxidant that has an affinity for the tissues of the prostate.
Note that antioxidants block the initiation phase of cancer development, and usually the phases of promotion and progression, as well. Once there is a full-blown cancer, however, things become a lot more complicated. These are issues that you should discuss directly with your doctor.
Antioxidants cannot protect you against all of the forms of toxic assault and this is the reason that the body has other forms of protection available. Although free radicals often initiate cancerous changes in cells, not all carcinogens are free radicals. In fact, most potential cancer-causing compounds are not free radicals and only develop their full ability to wreak havoc upon cellular DNA after the body has acted upon them. In activating these procarcinogens, our own detoxification system can be at fault. The liver uses a two-step enzymatic detoxification procedure to remove the bulk of toxins from the body, and both of these steps must be working up to par and in a synchronized fashion to properly eliminate poisonous compounds. Important support for these actions by the liver comes from supplements such as calcium D-glucarate, indole-3-carbinol and diindolylmethane (DIM), methyl donors (including S-adenosyl methionine/SAMe and trimethylglycine/ TMG) and enzyme building blocks, such as N-acetyl-cysteine (NAC). These compounds play roles in the Phase I and Phase II enzyme detoxification pathways.
Ten Top Anti-Cancer Compounds
Catechins—Found in most concentrated form green tea, these are antioxidants and free radical scavengers. Chinese herbalism considers green tea to have an affinity for the liver.
Ellagic Acid—This polyphenol antioxidant and anticancer compound is most commonly found in certain fruits, especially, strawberries, raspberries, and blackberries, but also in grapes and apples.
Glutathione—The mineral selenium’s anticancer benefits depend in large part on its effect upon the body’s production of the powerful antioxidant detoxifier glutathione. Prostate cells that become cancerous typically have a defect in glutathione production. Good sources of glutathione and its building blocks are undenatured whey protein, asparagus, broccoli, and watermelon.
Indoles—Indole-3 carbinole, sulforophane, calcium-D glucarate and diindolylmethane (DIM) serve to either stimulate the production of Phase II detoxification enzymes and/or to prevent the reabsorption of toxic compounds which the body has processed for elimination. Good sources are cruciferous vegetables, such as broccoli, sprouts and other cabbage-family members.
Isoflavones—The best known of the isoflavones are genistein and daidzein from soybeans. Other good sources include red clover and various legumes. The isoflavones reduce the impact of toxic estrogen-like chemicals and may slow the division of cancer cells.
Lignans—These have antiestrogen activity and can protect against hormonal cancers. The most concentrated food sources are flax seeds and sesame seeds. Lycopene and other Carotenoids—Lycopene is the substance found in the everyday diet, which has the best record in preventing the development of prostate cancer. Some other important carotinoids are cryptoxanthin, zeaxanthin and lutein. Those supplementing the most common carotenoid, betacarotene, should take extra vitamin E as gamma-tocopherol and should not consume alcohol.
Proanthocyanidins—These polyphenolic compounds are the primary active ingredients in grape seed extracts and, along with resveratrol, are the most powerful protective compounds found in the red wine of the “French Paradox.” They are antioxidants and help to protect the arteries, prevent the oxidation of LDL cholesterol, reduce blood pressure and slow the invasion of cells by viruses. In vitro tests have shown protection against some forms of cancer and against cancer inducers.
Sulfur Compounds—The isothiocyanates found in cruciferous vegetables and the allyl sulfides and related compounds found in garlic are sulfur-containing compounds, which promote the glutathione-5-transferase enzyme system of detoxification and antioxidant protection. These compounds improve immune function.
Terpenes—These include limonoids, such as D-limonene, and technically might be considered to include the carotenoids, as well. They are excellent antioxidants. D-limonene also activates the liver’s Phase II enzyme system and is useful against some cancers.
The Liver and Phase I and II Detoxification
In Phase I of the liver’s detoxification process, the cytochrome P450 enzymes make fat-soluble toxins more water-soluble. This helps to prevent toxic compounds from being stored in fatty tissues and makes it easier for them to be excreted from the body. The fifty to one hundred enzymes involved in the Phase I system prepare potential carcinogens for elimination by the Phase II system. In a process known as “conjugation,” the Phase II system commonly uses enzymes to bind directly to the compounds that have been changed in Phase I, thus inactivating them. These conjugated (bound) toxins are then excreted. Most of the environmental toxins which we encounter are fat-soluble compounds with hormonal actions (such as estrogen-like compounds in our air and food), and these must be eliminated through the actions of the Phase I enzymes.
Unfortunately, Phase I system enzymes sometimes make poisonous compounds even more active as carcinogens until these compounds are fully conjugated. Water-soluble toxins, for instance, are more effective at gaining access to the DNA genetic element of the cells. Therefore, for protection against the initiation of cancers, the Phase II enzymes, the enzymes which are directly involved in the excretion of toxins from the system, must always be working as actively as are the Phase I enzymes. Important Phase II enzymes include the glucuronic acid, glutathione and sulfate systems. Glutathione is widely known to be a major antioxidant and has further actions as part of the glutathione-S-transferases. Low levels of glutathione in the body are almost always a sign of illness, especially of poor immune function.
Another Phase II enzyme of special importance is glucuronic acid. Glucuronic acid, via a process called glucoronidation, is important for binding the toxic metabolites of the body’s steroid hormones (estradiol, progesterone, and testosterone). Similarly, sulfate is active as a component in the sulfotransferases. These compounds work by preventing our bodies from reabsorbing the toxic substances that have already been processed for elimination from the body.
Many of the benefits the Phase II enzymes were discovered first by studying the health benefits of eating certain vegetables. Remember broccoli? The anti-cancer benefits of broccoli and other cruciferous vegetables have been documented for many years. One study performed in Buffalo, New York in the mid-1970s showed that the regular consumption of these vegetables dramatically reduced the incidence of colon and rectal cancer. Protection against these malignancies was dose-dependent—the more of these vegetables eaten, the more protection. Consuming several servings of cruciferous vegetables per week would go a very long way towards making these two forms of cancer into endangered species in Americans. Reviews of the benefits of dark-green vegetables have concluded that broccoli is amongst the most common items in the diets of individuals and populations with very low rates of gastrointestinal tract cancers, that is, cancers ranging from those of the esophagus and stomach to those of the colon and rectum. Other studies have shown broccoli’s protective effects against lung and breast cancers as well.
Much of the work done on broccoli and its cousins has focused upon the impact of indoles and dithiolthiones. These compounds appear to activate the cellular Phase II enzymes described above. Even highly potent toxins, for instance, aflatoxin, are prevented from doing damage to cellular DNA when these enzymeactivators are fed to test animals. Both glutathione and the enzymes that attach the glutathione to carcinogens are increased by the presence of indoles and dithiolthiones. The more recent discoveries regarding broccoli’s anti-cancer constituents highlight the role of the chemical sulforaphane, which like indoles and dithiolthiones, has been shown to raise the levels of Phase II enzymes. Sulforaphane exerts a number of direct effects on cancer cells, as well, and these benefits have encouraged the development of a large and growing body of research.
There are several ways in which the effectiveness of Phase II enzymes can be increased. The first is by supplying “building blocks” for these enzymes so that the body can make more of them, in particular glutathione. Probably the easiest way to do this with supplements is to take approximately 750 milligrams of N-acetyl-cysteine (NAC) per day as a supplement. (Do not exceed this amount unless directed to do so by your physician.) (Glutathione itself is very poorly absorbed by most individuals.) Other compounds seem to directly stimulate the production of Phase II compounds. Among these is indole-3-carbinol. The citrus oil extract D-limonene is already on the market and is a potent stimulant to Phase II enzyme production. Individuals who consume concentrated undenatured whey protein are taking advantage of yet another source of building blocks for Phase II enzymes. Whey contains a particular set of fractions from milk that dramatically increase the body’s ability to produce glutathione and does not have the drawbacks that are true of the other milk components when it comes to prostate cancer. The chief problem with whey is that all of the hormones and antibiotic residues typically found in modern dairy practices must be removed. Unfortunately, most of the commercial colostrum/ whey products currently available are contaminated and should be avoided.
A second approach is to supplement with compounds that indirectly increase the building blocks of Phase II enzymes while performing other important functions in the body. Remember the benefits of methyl groups discussed earlier? Methyl donors such as SAMe (S-adenosyl-methionine) and, especially, TMG (trimethyl glycine) indirectly produce much of the body’s cysteine for glutathione synthesis and also influence the availability of sulfate and the amino acid taurine. Methyl donors further protect the DNA through mechanisms that do not involve Phase II enzymes.
Finally, the supplements calcium Dglucarate and diindolylmethane (DIM) improve the effectiveness of Phase II enzymes through increasing their amounts or their degree of activity in the pathway of glucuronidation, and also by preventing conjugated toxins from being freed by bacterial action in the intestines. Calcium D-glucarate serves to block the unwanted actions of the beta-glucuronidases, enzymes that reverse the conjugation of the Phase II enzymes and allow toxins to be reabsorbed into the body. Thus calcium D-glucarate and diindolylmethane (DIM) might be viewed as the perfect complements to supplements that increase Phase II enzyme activity: it helps to insure that the toxins which the Phase II enzymes have conjugated and bound for excretion do not somehow find their way back into our systems.