~Cancer Adjuvant Therapy, Part 5


Selenium--is protective against many types of cancers, promotes apoptosis, is a powerful antioxidant, and improves quality of life during aggressive cancer therapies

Many animal studies have been conducted to evaluate the effects of super nutritional levels of selenium on experimental carcinogenesis using chemical, viral, and transplantable tumor models. Two thirds of these studies found that high levels of selenium reduced the development of tumors at least moderately (14-35% compared to controls) and, in most cases, significantly (by more than 35%) (Whanger 1998).

The impact of selenium supplementation on basal cell carcinoma was studied on 1312 subjects (18-80 years of age, 75% of whom were men) (Clark et al. 1996). Within 6-9 months, the group receiving 200 mcg a day of selenium realized about a 67% increase in plasma selenium levels. The non-supplemented group, although judged "normal" in regard to plasma selenium levels, experienced twice the rate of cancer as those receiving selenium. Researchers concluded that higher amounts of dietary selenium than the amount recommended by the FDA are needed to prevent cancer.

Although the study failed to show the effectiveness of selenium in altering the course of either basal or squamous cell carcinoma, selenium impacted the incidence of other types of malignancies with amazing success. The overall reduction in cancer incidence was 37% in the selenium-supplemented group; a 50% reduction in cancer mortality was observed over a 10-year period (Clark et al. 1996).

The following are the site-specific reductions in cancer incidence observed in the study: colorectal cancers (58%), lung cancer (46%), and prostate cancer (63%). A selenium deficiency appears to increase the risk of prostate cancer four- to five-fold. It was determined that as the male population ages selenium levels decrease, paralleling an increase in prostate cancer (Brooks et al. 2001).

Data is compelling regarding the usefulness of selenium’s protective effects against cancer:

  • Selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats (Davis et al. 2002). Note: While selenium is contributing to the lower incidence of malignancy, the anticancer affects of broccoli should also be factored into the defense. Please read the section What Should the Cancer Patient Eat (appearing in this protocol) for valuable information regarding dietary factors affecting patient outcome.

  • The relationship between serum levels of selenium and the development of upper digestive tract cancer was examined (Mark et al. 2000). The relative risk of esophageal cancer was 0.56 in individuals in the highest quartile of selenium level compared with those in the lowest quartile. The corresponding relative risk of gastric cardia cancer was 0.47. Based on the data, it was concluded that 26.4% of esophageal and gastric cardia cancers are attributable to low selenium levels.

  • Adding selenium to salt resulted in a significant reduction in the incidence of cancer (Whanger 1998).

  • A significant increase in apoptosis and a decrease in DNA synthesis in breast cancers cells (MCF-7 and SKBR-3) occurred with selenium supplementation. The selenium benefit was just as impressive in cancers of the lung (RH2), small intestine (HCF8), colon (Caco-2), and liver (HepG2). Prostate cancers (PC-3 and LNCaP) as well as colon cancer (T-84), although initially less affected by supplementation, became responsive when selenium was coadministered with Adriamycin or Taxol (Vadgama et al. 2000). This study suggests that selenium potentiates the anti-cancer effects of chemotherapy. Selenium supplementation in patients undergoing radiation therapy for rectal cancer improved quality of life and reduced the appearance of secondary cancers (Hehr et al. 1997).

  • It appears that selenium acts as an immunologic response modifier, normalizing every component of the immune system (Ferencik et al. 2003; Arthur et al. 2003)

An important form of selenium is Se-methylselenocysteine. This is the form of selenium found naturally in plants such as broccoli and garlic. A suggested selenium dosage is 200 mcg a day. The optimal dose for cancer patients is unknown at this time, but suggestions have ranged from 200-400 mcg a day depending upon the selenium content of the soil. Foods considered good sources of selenium include Brazil nuts, grains, onions, tomatoes, broccoli, chicken, eggs, garlic, liver, seafood, and wheat germ. Americans typically consume 60-100 mcg of selenium a day from dietary sources.

Silibinin (from milk thistle)--has antioxidant activity, increases sensitivity to chemotherapy while reducing its side effects, assists in arresting the growth of cancer, promotes differentiation, inhibits COX-2 enzyme, and suppresses NF-kB

Fourteen years ago, the Life Extension Foundation introduced silymarin, a hepato-protective herb, to members. The major active constituent of silymarin is silibinin; a long-recognized antioxidant with more recently ascribed anticarcinogenic traits. Silibinin inhibits the growth of various cancer cell lines. The silibinin acts synergistically with cisplatin and doxorubicin, common chemotherapeutic drugs, improving their efficacy. By arresting tumor cell division at a strategic stage, silibinin appears to make tumor cells more sensitive to chemotherapy. Also, the harsh side effects associated with cytotoxic chemicals are less damaging when silibinin is utilized (Bokemeyer et al. 1996).

Milk thistle is described as an adaptogenic herb. For example, it encourages new cell growth where repair is needed but arrests cell division in tumor tissue; it increases the activity of certain enzymes but inhibits others. Milk thistle inhibits COX-2 (Zhao et al. 1999). Note: Go to Cyclooxygenase (COX-2) Inhibitors (Naturally Occurring) appearing in this protocol for other nutraceuticals capable of inhibiting the COX-2 enzyme. Also, consult Cyclooxygenase Inhibitors in the protocol entitled Cancer Treatment: The Critical Factors to learn more about the COX-2-cancer connection.

Silibinin arrests cell growth in the early phase of the cycle known as G1, a period of growth before DNA replication. Silibinin discourages cell growth by inhibiting various kinase enzymes (those playing a pivotal role in regulatory mechanisms), enabling a critical stage in cellular development referred to as differentiation. Differentiated cells abandon their primitive façade and assume the physical likeness and behavioral patterns of healthy cells. In fact, silibinin caused differentiation of a significant number of malignant prostate cells to more normal cells, while simultaneously decreasing PSA levels (Zi et al. 1999).

Silibinin inhibits growth of drug-resistant breast and ovarian cancer lines. It binds to type II estrogen binding sites, an action that turns off the proliferative effects of the cell (Scambia et al. 1996). In addition, silymarin inhibited the secretion of VEGF (an angiogenic factor) by malignant cells, thwarting the formation of cancer's vascular network (Jiang et al. 2000).

Silymarin potently suppressed NF-kB, but did not affect TNF-alpha-induced NF-kB, demonstrating a pathway-dependent inhibition by silymarin. It appears the inhibitory effect of silymarin on NF-kB activation is associated with its liver-protecting properties. Suppression of NF-kB, a key regulator in inflammatory and immune reactions, significantly improves the anticarcinogenic status of silymarin (Saliou et al. 1998).

Silymarin/silibinin is remarkable medicine for the liver. Numerous studies show that milk thistle is effective in treating virtually every type of liver disease, including cirrhosis and alcohol or chemical-induced liver damage (Jacobs et al. 2002; Flora et al. 1998). So worthy is the herb in protecting against life-threatening toxins that individuals poisoned by the Amanita mushroom survived when silibinin was utilized (Carducci et al. 1996). A healthy liver is essential to detoxification, a process key to restoring health to cancer patients.

Standardized milk thistle extract usually consists of 35% silibinin, whereas the silymarin concentrate used in Europe contains a minimum of 80% silibinin. The Life Extension Foundation recommends the highly beneficial 80% silibinin extract. A suggested therapeutic dosage of Silibinin Plus is up to 6 capsules daily (1950 mg a day). For protection, use about 1-2 capsules (325-650 mg a day).

Soy--is protective against certain malignancies, appears to be an alternative to signal transduction-inhibiting drugs, and inhibits angiogenesis, cell proliferation, and metastasis.

  • Isoflavones
  • For Prostate Cancer
  • For Breast Cancer
  • Soy and Other Types of Cancer
  • Free-Radical Scavenging Effects
  • Soy Precautions and Dosage

Legumes, including the soybean, contain bioactive compounds classified broadly as phytoestrogens as opposed to estrogens. Phytoestrogens are nonsteroidal and can actually inhibit steroids such as aromatase. Most have little or no estrogenic activity. When others have such activity, it is usually beneficial and specific to a certain tissue. For example, some soy isoflavones (a type of phytoestrogen) benefit bone but do not affect the kidney. In pharmacology terms, this is called a selective estrogen receptor modulator (SERM). A compound in soy, genistein, is a natural SERM. Tamoxifen and Raloxifen are chemical SERMs (Setchell et al. 1999).

The most recent studies suggest that the reason that different estrogens have different effects on different tissues is because there is more than one type of estrogen receptor. So far, three variations of the estrogen receptor have been found: one alpha and two betas. They share similar estrogen structure. The estrogen receptor-receptor (ERb) may suppress the action of the estrogen receptor-alpha (ERa) - at least in cancer cells (Maruyama et al. 2001; Saji et al. 2002; Speirs et al. 2002). And, growth-promoting estrogens such as estradiol activate ERa. Phytoestrogens preferentially activate the ERb, which is repressive (Barkhem et al. 1998). For this reason, phytoestrogens have been characterized as good estrogens, and whatever estrogenic effect they have (which is estimated to be 1000-10,000 times weaker than estradiol, where it exists) may be nullified by their inhibition of estrogen synthesis and repression of the receptor that allows estradiol into the cell (Shao et al. 2000).

In normal tissue, the two estrogen receptors apparently work together to control both the amount and the use of estrogen in the body. It has been demonstrated that some types of cancer cells lose one type of estrogen receptor, leaving the control mechanism inoperable (Iwao et al. 2000; Sampath et al. 2001). This has been demonstrated in prostate cancer. Some types of prostate cancers do not express their ERa and some lose beta. This is why some will respond to estrogen and stop growing and others will stop growing when an anti-estrogen, such as genistein or Tamoxifen, is added.

The loss or gain of estrogen receptors occurs because of methylation abnormalities that occur in DNA (Lau et al. 2000). DNA methylation abnormalities are caused by three known factors: poor diet (i.e., a diet lacking in methylation factors including folate, vitamins B6 and B12), chemicals, and age.

Phytoestrogens include many diverse plant compounds, including resveratrol from grapes (Kopp 1998), curcumin from roots (Jaga 2001), and polyphenols from tea leaves (Mazur 1998). It is a very broad category that is further broken down into dozens of classifications such as flavonoids and flavones. The anticancer effects of phytoestrogens are the subject of dozens of scientific studies (Adlercreutz 1995).

Soy Isoflavones

Soy contains phytoestrogens known as isoflavones, including daidzein, coumestrol, and genistein. Isoflavone supplements contain a mixture of many different types of these compounds. Interest in their anticancer potential stems from the lower occurrence of hormone-related cancers in Asians who eat a lot of soy. It is doubtful that the low rates of breast, prostate, and other hormonally related cancers are due solely to soy, but studies show that compounds isolated from soy have significant anticancer effects (Suthar et al. 2001).

Soy for Prostate Cancer

The most dangerous aspect of prostate cancer is metastasis (spreading to other areas). Prostate cancer can be controlled if it can be limited to the prostate gland. Unfortunately, many men with prostate cancer have undetected metastases.

Genistein has powerful and specific effects against the spread of prostate cancer. Genistein significantly activated 832 genes in prostate cancer cells, 13 of which are related to metastasis (Li et al 2002a,b; Sarkar et al. 2002).

Genistein down-regulated multiple genes that dissolve surrounding tissue to enable metastasis and invasion of surrounding tissue, and down-regulated genes that create new tumor blood vessels. Genistein also affected genes important in stopping the cell cycle, differentiation, apoptosis, and cell signaling communication (Li et al. 2002a).

Genistein has "potent anti-proliferative effects" against human prostate cells (Shen et al. 2000), and inhibits metastasis (Schleicher et al. 1999). Genistein is one component of soy. Soy has powerful effects in the prevention and eradication of prostate cancer. Different components of soy have different effects against prostate cancer cells. Genistein blocks an enzyme that destroys an anticancer vitamin D metabolite in cancer cells (Farhan et al. 2002).

Prostate cancer is a hormone-related cancer. In a study mice were fed three different soy products: soy protein without isoflavones, soy phytochemical concentrate (a combination of genistein, daidzein, glycitein, and other compounds), and genistein. All three feeds had a positive effect on hormones as they relate to prostate cancer growth. The androgen receptor, which correlates with tumor weight, was reduced 42% by soy protein. Genistein reduced serum dihydrotestosterone, a form of testosterone associated with hyperplasia and cancer, and caused a 57% reduction in tumor growth. Soy phytochemical concentrate inhibited the overall growth of prostate cancer by 70%. Soy phytochemical concentrate also stopped metastases to lymph nodes and lung. Cell death was induced, and angiogenesis was significantly inhibited (Zhou et al. 2002).

Healthy, normal rodents fed genistein for 2 weeks at a dietary level had significant reductions in androgen and the two estrogen receptors (Fritz et al. 2002). Minimizing the number of hormone receptors reduces levels of cell growth-promoting hormones in the prostate gland. The levels of phytoestrogens in 25 men with and without benign prostatic hyperplasia (BPH), a noncancerous overgrowth of prostate cells, were examined. Genistein levels in men with BPH were significantly lower than in those without BPH (Hong et al. 2002). Adding genistein to prostate tissue taken from men with BPH stops the prostate cancer growth (Geller et al. 1998).

Various soy diets have significant effects against prostate cancer compared to a casein (milk protein) diet. Soy significantly reduced insulin-like growth factor (IGF-1), a protein that helps tumors create blood vessels. Blood vessel density and tumor cell proliferation were decreased. Cell death was increased. Dietary soy works through "a combination of direct effects on tumor cells and indirect effects on tumor neovasculature" (blood vessels) (Zhou et al. 1999). The cell-killing effects of soy components are important not only for men who have been diagnosed with prostate cancer, but for healthy men as well.

Prostate-specific antigen (PSA) is elevated in men with prostate enlargement. PSA is regulated by androgens. Genistein and its precursor, biochanin A, markedly decrease PSA in prostate cancer cells by inactivating testosterone (Sun et al. 1998). A study on rats showed a 38% decline in PSA, along with a significant reduction in metastases when genistein was given subcutaneously (Schleicher et al. 1999; Zand et al. 2002).

The ability of genistein to reduce cellular proliferation in men with elevated PSA is currently under investigation. In addition, the ability of supplemental soy to lower PSA and kill cancer cells in men with localized prostate cancer is being studied. The ability of soy isoflavones to modulate hormones and cancer-related proteins in men with prostate cancer is also being studied.

Population-based studies have shown that men with high levels of soy and other isoflavones in their blood have the lowest risk of prostate cancer. In a study on men from Japan, China, and the United States, it was shown that legumes, including soy, reduce the incidence of prostate cancer by 38%. Eating yellow-orange vegetables reduces it 33%, and cruciferous vegetables reduce it 39%. These findings are consistent across ethnicities, indicating that isoflavones, not genes, are responsible for the reductions in risk (Kolonel et al. 2000). An analysis of data collected from 12,395 Seventh-Day Adventist men indicates that more than one serving per day of soymilk can reduce the risk of prostate cancer 70% (Jacobsen et al. 1998). Note: Seventh-Day Adventists are vegetarians; meat is a known risk factor for prostate cancer. Maintaining a vegetarian diet may have contributed to the low rates of prostate cancer.

Genistein down-regulates proteins that enhance prostate cancer growth, including HER2 neu. Genistein has no adverse toxicity, and the amount needed to reduce the proteins by half is achieved with supplemental genistein or a diet high in soy products. Genistein inhibits EGF signaling pathway suggesting that this phytoestrogen may be useful in both protecting against and treating prostate cancer (Dalu et al. 1998).

Soy isoflavones clearly work against prostate cancer through several mechanisms, including modulating hormones, blocking metastasis, interfering with cell signaling, stopping cell growth, inducing cell death, and possibly activating and deactivating cancer-related genes.

Soy for Breast Cancer

Soy phytoestrogens help to prevent and control hormone-related breast cancer (Zhou et al. 2004; Adlercreutz 2002). It is especially beneficial for Western women, who are exposed to a comparatively high level of environmental estrogens. Soy is anti-estrogenic. It prevents the conversion of estrone to 17-beta-estradiol. Estradiol fuels the growth of breast cancer, whereas estrone is a weaker estrogen. Genistein causes cancer cells to metabolize estradiol to estrogenically weaker or inactive metabolites (Brueggemeier et al. 2001).

Soy phytoestrogens naturally activate the receptor, known as ERb, which in turn suppresses the activation of ERa and allows growth-promoting estradiol into cancer cells (Pettersson et al. 2000). ERa is the receptor referred to as "estrogen receptor positive;" "estrogen receptor negative" breast cancer cells have estrogen ERb. Estrogen receptor positive cells have lost their beta-receptors during the events leading to breast cancer. Normal cells have both types of estrogen receptors.

Genistein naturally activates ERb, inhibiting cell proliferation. Activating the beta-receptor down-regulates the alpha-receptor, or estradiol-activated, receptor. This negates estradiol's cancer-promoting effects.

The consumption of soy reduced the risk of having ERa positive breast cancer by 56%, whereas the effect on both types of breast cancer was 30% (Dai et al. 2001).

Genistein interferes with cancer's ability to grow blood vessels. A direct link between alpha-receptors and angiogenesis has been discovered in estrogen receptor positive cancer cells (MCF-7). These cells have too many alpha-receptors and not enough beta-receptors. When estradiol attaches to the alpha-receptors, it activates a protein that promotes the formation of new blood vessels (Sampath et al. 2001). Genistein blocks the formation of new blood vessels (Zhou et al. 1998; Wietrzyk et al. 2001). Furthermore, genistein prevents vitamin D from being degraded by cancer cells (Farhan et al. 2002).

In a study on estrogen receptor positive breast cancer cells (MCF-7), genistein competed successfully with estradiol for access to the cells, and once inside, blocked estradiol from inducing cell growth. In a study on Japanese women who drank soymilk containing 100 mg of isoflavones a day, estrone and estradiol levels fell by almost 30% (Nagata et al. 1998).

Breast cancer cells have elevated levels of enzymes that produce estradiol. One of the enzymes, known as 17-beta-hydroxysteroid dehydrogenase type 1 (17HSD1), causes the conversion of "weak estrogen" (estrone) to "strong estrogen" (estradiol) and helps cancer cells grow. A variant known as 17HSD2 does the opposite. Breast cancer cells have elevated amounts of 17HSD1, and insufficient 17HSD2 (Miyoshi et al. 2001). Studies show that if cancer cells are treated with genistein, 17HSD2 will be made, and "strong estrogen" (estradiol) will be converted to "weak" (estrone) (Hughes et al. 1997). A woman with breast cancer may have the same level of estrogen in her blood as a woman without breast cancer. The elevated estradiol levels occur inside cancer cells where abnormalities create imbalances in enzymes. Such 17HSDvariances favor the accumulation of estrogen for cell growth.

Genistein also inhibits an enzyme that is elevated in breast cancer cells known as "aromatase" (Kao et al. 1998; Breuggemeier et al. 2001). Aromatase helps convert testosterone to estrogen. Elevated male hormones, enlarged prostate, and abnormal cell growth do not promote prostate cancer in mice that lack aromatase (McPherson et al. 2001).

Asian women get early protection by eating soy their entire lives (Lamartiniere et al. 1998). The genistein in soy promotes more differentiated tissue in the breast, which leaves less tissue that can become cancerous. Soy isoflavones decrease density in the breast enabling easier detection of cancer by mammogram (Maskarenic et al. 2001). A serving of tofu every week decreases the risk of breast cancer by 15% (Wu et al. 1996). It is well-established that when Asian women abandon their traditional diet, their risk of breast cancer escalates. It is important to realize, however, that while it has been proven that soy components have direct and powerful effects against cancer cells, it cannot be assumed that soy alone is responsible for the reduced risk of hormone-related cancers in Asians. There are many aspects of the Asian diet that undoubtedly play a role, including the low consumption of animal fat. Green tea is another component of the Asian diet that has proven anticancer effects. A polyphenol from black tea has no effect on prostate cancer cells. However, when combined with genistein, it stops proliferation (Sakamoto 2000).

HER2/neu and EGFR are both related to breast cancers resistant to treatment with tamoxifen and other therapies (Ross et al. 1998). Genistein blocks an enzyme that promotes the proliferation of cancer cells. Because protein tyrosine kinases activate other cancer-promoting factors, genistein is a very attractive candidate for the prevention and treatment of various types of cancer. A dietary amount of the soy compound genistein significantly delayed the appearance of the HER2/neu-type cancer. It did not, however, reduce tumor size or number in this study (Jin et al. 2002).

It is important to note that DDT and other chlorine-related chemicals activate tyrosine kinases (TK), including HER2/neu-related ones in human cancer cells. Although DDT was banned decades ago, Americans are still being exposed to it. Genistein and other isoflavones block the activation of TK by DDT and related estrogen-mimicking chemicals, but tamoxifen does not (Enan et al. 1998; Verma et al. 1998).

A mouse study shows that increasing amounts of genistein retard cancer growth, in accordance with the cell studies (Shao et al. 1998). The animals must be implanted with estradiol to make the cancer cells grow (Santell et al. 2000; Allred et al. 2001; Ju et al. 2001). When mice are fed the equivalent of what Asians usually consume in their diets, the appearance of a genetic type breast cancer (as opposed to a chemically induced one) is significantly delayed by genistein, soy isoflavones, and daidzein, another soy compound (Jin et al. 2002).

Studies in monkeys, the closest animal model to humans, show that soy phytoestrogens impede the proliferation of cells responsive to estrogen. "Soybean phytoestrogens are not estrogenic at dietary doses" (Cline et al. 2001). Statistics on the rate of hormone-related cancers in Asians prove that soy is extremely beneficial against hormone-related cancers in humans. They show that people who eat large amounts of soy products have the lowest levels of strong estrogen in their bodies and the lowest rates of breast and prostate cancers.

Continued . . .

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