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Cancer Adjuvant Therapy
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
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 theERb, 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 ERaand 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 duringthe 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.
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