Alternative Medicine Review, 5(4):372-375, 2000
Description and Constituents
Tea is one of the most widely consumed beverages
in the world today, second only to water, and its medicinal properties
have been widely explored. The tea plant, Camellia sinensis, is
a member of the Theaceae family, and black, oolong, and green tea
are produced from its leaves. It is an evergreen shrub or tree and
can grow to heights of 30 feet, but is usually pruned to 2-5 feet
for cultivation. The leaves are dark green, alternate and oval,
with serrated edges, and the blossoms are white, fragrant, and appear
in clusters or singly. Unlike black and oolong tea, green tea production
does not involve oxidation of young tea leaves. Green tea is produced
from steaming fresh leaves at high temperatures, thereby inactivating
the oxidizing enzymes and leaving the polyphenol content intact.
The polyphenols found in tea are more commonly known as flavanols
or catechins and comprise 30-40 percent of the extractable solids
of dried green tea leaves. The main catechins in green tea are epicatechin,
epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate
(EGCG), with the latter being the highest in concentration. Green
tea polyphenols have demonstrated significant antioxidant, anticarcinogenic,
anti-inflammatory, thermogenic, probiotic, and antimicrobial properties
in numerous human, animal, and in vitro studies.1,2
Mechanisms of Action
The anticarcinogenic properties of green
tea polyphenols, mainly EGCG, are likely a result of inhibition
of biochemical markers of tumor initiation and promotion, induction
of apoptosis, and inhibition of cell replication rates, thus retarding
the growth and development of neoplasms.3,4 Their antioxidant potential
is directly related to the combination of aromatic rings and hydroxyl
groups that make up their structure, and is a result of binding
and neutralization of free radicals by the hydroxyl groups. In addition,
green tea polyphenols stimulate the activity of hepatic detoxification
enzymes, thereby promoting detoxification of xenobiotic compounds,
and are also capable of chelating metal ions, such as iron, that
can generate radical oxygen species.5,6
Green tea polyphenols inhibit the production
of arachidonic acid metabolites such as pro-inflammatory prostaglandins
and leukotrienes, resulting in a decreased inflammatory response.
Human and animal studies have demonstrated EGCG's ability to block
inflammatory responses to ultraviolet A and B radiation as well
as significantly inhibiting the neutrophil migration that occurs
during the inflammatory process.7-9
Research on green tea's thermogenic properties
indicates a synergistic interaction between its caffeine content
and catechin polyphenols may result in prolonged stimulation of
thermogenesis. Studies have also shown green tea extracts are capable
of reducing fat digestion by inhibiting digestive enzymes.10,11
Although the exact mechanism is unknown, green tea catechins have
been shown to significantly raise levels of Lactobacilli and Bifidobacteria
while decreasing levels of numerous potential pathogens.12 Studies
have also demonstrated green tea's antibacterial properties against
a variety of gram-positive and gram-negative species.13
Several studies have demonstrated green tea polyphenols' preventative
and inhibitory effects against tumor formation and growth. While
the studies are not conclusive, green tea polyphenols, particularly
EGCG, may be effective in preventing cancer of the prostate, breast,
esophagus, stomach, pancreas, and colon.14 There is also some evidence
that green tea polyphenols may be chemopreventative or inhibitory
toward lung, skin, and liver cancer,15-17 bladder and ovarian tumors,18,19
leukemia,20 and oral leukoplakia.21
Many chronic disease states and inflammatory conditions are a result
of oxidative stress and subsequent generation of free radicals.
Some of these include heart disease (resulting from LDL oxidation),
renal disease and failure, several types of cancer, skin exposure
damage caused by ultraviolet (A and B) rays, as well as diseases
associated with aging. Green tea polyphenols are potent free radical
scavengers due to the hydroxyl groups in their chemical structure.
The hydroxyl groups can form complexes with free radicals and neutralize
them, preventing the progression of the disease process.22
Recent studies on green tea's thermogenic properties have demonstrated
a synergistic interaction between caffeine and catechin polyphenols
that appears to prolong sympathetic stimulation of thermogenesis.
A human study of green tea extract containing 90 mg EGCG taken three
times daily concluded that men taking the extract burned 266 more
calories per day than did those in the placebo group and that green
tea extract's thermogenic effects may play a role in controlling
obesity.23 Green tea polyphenols have also been shown to markedly
inhibit digestive lipases in vitro, resulting in decreased lipolysis
of triglycerides, which may translate to reduced fat digestion in
Intestinal Dysbiosis and Infection:
A small study in Japan demonstrated a special green tea catechin
preparation (30.5% EGCG) was able to positively affect intestinal
dysbiosis in nursing home patients by raising levels of Lactobacilli
and Bifidobacteria while lowering levels of Enterobacteriaceae,
Bacteroidaceae, and eubacteria. Levels of pathogenic bacterial metabolites
were also decreased.12 An in vitro study also demonstrated green
tea's antimicrobial activity against a variety of gram-positive
and gram-negative pathogenic bacteria that cause cystitis, pyelonephritis,
diarrhea, dental caries,24 pneumonia, and skin infections.13
Sickle cell anemia is characterized by a population of "dense
cells" that may trigger vaso-occlusion and the painful sickle
cell "crisis." One study demonstrated that 0.13 mg/mL
green tea extract was capable of inhibiting dense-cell formation
by 50 percent.25 Another potential therapeutic application of green
tea is the treatment of psoriasis. The combination therapy of psoralens
and ultraviolet A radiation is highly effective but has unfortunately
been shown to substantially increase the risk for developing squamous
cell carcinoma and melanoma. An in vitro study using human and mouse
skin demonstrated that pre- and post-treatment with green tea extract
inhibited DNA damage induced by the psoralen/ultraviolet A radiation
Dosage and Toxicity
Green tea is generally considered a safe,
non-toxic beverage and consumption is usually without side-effects.
The average cup of green tea, however, contains from 10-50 mg of
caffeine and overconsumption may cause irritability, insomnia, nervousness,
and tachycardia. Because studies on its possible teratogenic effect
are inconclusive, caffeine consumption is contraindicated during
pregnancy. Lactating women should also limit caffeine intake to
avoid sleep disorders in infants.26
The dosage for green tea beverage varies,
depending on the clinical situation and desired therapeutic effect.
The phenolic content of green tea infusion is between 50-100 mg
polyphenols per cup, depending on species, harvesting variables,
and brewing methods,27 with typical dosages ranging from 3 to 10
cups per day. Cancer preventative effects are usually associated
with dosages in the higher end of the range.28 Green tea extracts
standardized to 80-percent total polyphenols are dosed at an average
of 500-1500 mg per day.
L. Grean Tea: Healing tonic. Am J Natur Med 1998;5:28-31.
HN. Green tea composition, consumption, and polyphenol chemistry.
Prev Med 1992;21:334-350.
A, Hasan M. Green tea polyphenols and cancer: biological mechanisms
and practical implications. Nutr Rev 1999;57:78-83.
N, Feyes DK, Nieminen AL, et al. Green tea constituent epigallacatechin-3-gallate
and induction of apoptosis and cell cycle arrest in human carcinoma
cells. J Natl Cancer Inst 1997;89:1881-1886.
M, Ghiselli A, Ferro-Luzzi A. In vivo antioxidant effect of
green and black tea in man. Eur J Clin Nutr 1996;50:28-32.
D, Riso P, Colombo A, Testolin G. Supplementation of Jurkat
T cells with green tea extract decreases oxidative damage due
to iron treatment. J Nutr 1999;129:2130-2134.
SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant
(-)-epigallocatechin-3-gallate from green tea reduces UVB-induced
inflammatory responses and infiltration of leukocytes in human
skin. Photochem Photobiol 1999;69:148-153.
JF, Zhang YJ, Jin XH, et al. Green tea protects against psoralen
plus ultraviolet A-induced photochemical damage to skin. J Invest
R, Frass M, Gmeiner B, et al. The green tea extract epigallocatechin
gallate is able to reduce neutrophil transmigration through
monolayers of endothelial cells. Wien Klin Wochenschr 1999;111:276-282.
AG, Seydoux J, Girardier L, et al. Green tea and thermogenesis:
interactions between catechin-polyphenols, caffeine, and sympathetic
activity. Int J Obes Relat Metab Disord 2000;24:252-258.
American Journal of Clinical Nutrition
Vol. 71, No. 6, 1698S-1702s, June 2000
and Nihal Ahmad
Case Western Reserve University, Cleveland.
The tea plant Camellia sinesis is cultivated
in 30 countries. Epidemiologic observations and laboratory studies
have indicated that polyphenolic compounds present in tea may reduce
the risk of a variety of illnesses, including cancer and coronary
heart disease. Most studies involved green tea, however; only a
few evaluated black tea.
Results from studies in rats, mice, and
hamsters showed that tea consumption protects against lung, forestomach,
esophagus, duodenum, pancreas, liver, breast, colon, and skin cancers
induced by chemical carcinogens. Other studies showed the preventive
effect of green tea consumption against atherosclerosis and coronary
heart disease, high blood cholesterol concentrations, and high blood
Because the epidemiologic studies and research
findings in laboratory animals have shown the chemopreventive potential
of tea polyphenols in cancer, the usefulness of tea polyphenols
for humans should be evaluated in clinical trials. One such phase
1 clinical trial is currently under way at the MD Anderson Cancer
Center in collaboration with Memorial Sloan-Kettering Cancer Center.
This study will examine the safety and possible efficacy of consuming
the equivalent of >10 cups (>2.4 L) of green tea per day.
The usefulness of tea polyphenols may be
extended by combining them with other consumer products such as
food items and vitamin supplements. This "designer-item"
approach may be useful for human populations, but it requires further
Significant progress has been made in understanding
diseases that cause alarming mortality and morbidity in humans:
their processes, possible prevention, and therapies. Cancer and
coronary heart disease are the most important of these disorders.
Because of research efforts over the past 30 y, it is now well appreciated
that although the causes of the major diseases are diverse and countless,
changes in dietary habits and lifestyles may reduce their risk in
many cases. Research has indicated that many common foods have nonnutritive
components, commonly known as chemopreventive agents that may provide
protection against a variety of illnesses, including cancer and
coronary heart disease. One such class of agents is antioxidants.
The predominant mechanism of protective action of antioxidants appears
to be the destruction of free radicals.
The water extract of the dry leaves of the
plant Camellia sinesis, an evergreen shrub of the Theaceae family,
is a popular beverage commonly known as tea. A drink that contains
many compounds, including a mixture of polyphenols, tea has been
consumed by some human populations for many generations and, in
some parts of the world, has been considered to have health-promoting
potential (1). Extensive laboratory research and the epidemiologic
findings of the past 20 y have shown that polyphenolic compounds
present in tea may reduce the risk of a variety of illnesses.
CONSUMPTION, COMPOSITION, AND CHEMISTRY OF TEA
The tea plant C. sinensis is native to Southeast
Asia but is currently cultivated in >30 countries around the
world. Tea is consumed worldwide, although in greatly different
amounts; it is generally accepted that, next to water, tea is the
most consumed beverage in the world, with per capita consumption
of approximately 120 mL/d (2). Of the total amount of tea produced
and consumed in the world, 78% is black, 20% is green, and <2%
is oolong tea. Black tea is consumed primarily in Western countries
and in some Asian countries, whereas green tea is consumed primarily
in China, Japan, India, and a few countries in North Africa and
the Middle East. Oolong tea production and consumption are confined
to southeastern China and Taiwan (2).
Green, black, and oolong teas undergo different
manufacturing processes. To produce green tea, freshly harvested
leaves are rapidly steamed or pan-fried to inactivate enzymes, thereby
preventing fermentation and producing a dry, stable product. Epicatechins
are the main compounds in green tea, accounting for its characteristic
color and flavor.
For the production of black and oolong teas,
the fresh leaves are allowed to wither until their moisture content
is reduced to approximately 55% of the original leaf weight, which
results in the concentration of polyphenols in the leaves. The withered
leaves are then rolled and crushed, initiating fermentation of the
polyphenols. During these processes, the catechins are converted
to theaflavins and thearubigins. Oolong tea is prepared by firing
the leaves shortly after rolling to terminate the oxidation and
dry the leaves. Normal oolong tea is considered to be about half
as fermented as black tea. The fermentation process results in oxidation
of simple polyphenols to more complex condensed polyphenols to give
black and oolong teas their characteristic colors and flavors.
The composition of the tea leaves depends
on a variety of factors, including climate, season, horticultural
practices, and the type and age of the plant. The chemical composition
of green tea is similar to that of the leaf. Green tea contains
polyphenolic compounds, which include flavanols, flavandiols, flavonoids,
and phenolic acids and account for30% of the dry weight of green
tea leaves. Most of the polyphenols in green tea are flavanols,
commonly known as catechins; the major catechins in green tea are
(-)-epicatechin, (-)-epicatechin-3-gallate, (-)-epigallocatechin,
and (-)-epigallocatechin-3-gallate (EGCG). In black teas, the major
polyphenols are theaflavin and thearubigin.
TEA POLYPHENOLS AND THE RISK OF CANCER
Abundant experimental and epidemiologic
evidence accumulated mainly in the past decade from several centers
worldwide provides a convincing argument that polyphenolic antioxidants
present in green and black tea can reduce cancer risk in a variety
of animal tumor bioassay systems (2–4). Most of the studies
showing the preventive effects of tea were conducted with green
tea; only a few studies assessed the usefulness of black tea (2).
These studies showed that the consumption of tea and its polyphenolic
constituents affords protection against chemical carcinogen–
or ultraviolet radiation–induced skin cancer in the mouse
Tea consumption also affords protection
against cancers induced by chemical carcinogens that involve the
lung, forestomach, esophagus, duodenum, pancreas, liver, breast,
colon, and skin in mice, rats, and hamsters. We reviewed this area
of research (2), and the bioavailability of the polyphenols from
tea has been established by others (5). The relevance of the extensive
laboratory information for human health can be assessed only through
epidemiologic observations, however, especially in a population
with high cancer risk.
Much of the cancer-preventive effects of
green tea are mediated by EGCG , the major polyphenolic constituent
of green tea (2). One cup (240 mL) of brewed green tea contains
up to 200 mg EGCG. Many consumer products, including shampoos, creams,
drinks, cosmetics, lollipops, and ice creams, have been supplemented
with green tea extracts and are available in grocery stores and
The use of biochemical modulators in cancer
chemotherapy has been studied extensively (6). The adverse effects
of modulating drugs can be life threatening, and their use increases
the patient's medication burden as well. Thus, the substances used
in diet and beverages should be studied for their potential as biochemical
modulators that could increase the efficacy of therapy. In this
regard, Sadzuka et al (6) showed that the oral administration of
green tea enhanced the tumor-inhibitory effects of doxorubicin on
Ehrlich ascites carcinomas implanted in CDF1 and BDF1 mice. The
study showed that green tea treatment increases the concentration
of doxorubicin in tumor but not in normal tissue. If these observations
can be verified in human populations, they may have relevance to
TEA POLYPHENOLS AND THE RISK OF CORONARY HEART DISEASE
Coronary heart disease is most prevalent
in the Western world, probably as a result of the lifestyle in this
part of the world, which includes a diet high in saturated fats
and low physical activity, and the large proportion of the population
who smoke cigarettes and have high blood pressure. A variety of
epidemiologic studies showed the preventive effect of green tea
consumption against atherosclerosis and coronary heart disease (see
references 1 and 7 and the references therein). Tea consumption
has also been shown to reduce the risk of high blood cholesterol
concentrations and high blood pressure (8). In addition, studies
in experimental animals showed the preventive effect of green tea
against atherosclerosis (9).
EFFECTS OF TEA POLYPHENOLS AGAINST OTHER DISEASES
Many studies have shown that the consumption
of tea or its polyphenols can afford protection against diseases
other than cancer and coronary heart disease. A few of these studies
are as follows: Weisburger (10) showed that tea is protective against
stroke; Fujita (11) and Kao and P’eng (12) reported that tea
consumption lowers the risk of osteoporosis; Imai and Nakachi (13)
reported protection against liver disease; Horiba et al (14), Terada
et al (15), and Young et al (16) reported that tea consumption provides
protection against bacterial infection; and Nakayama et al (17)
and Tao (18) found that tea provides protection against viral infection.
ANTI-INFLAMMATORY EFFECTS OF TEA
In several studies from our laboratory and
elsewhere, the polyphenolic fraction from green tea was shown to
protect against inflammation caused by certain chemicals, such as
12-O-tetradecanoylphorbol-13-acetate, a principal irritant in croton
oil (2, 19, 20), or by ultraviolet radiation B (290–320 nm)
(21). Green tea has also been shown to be effective against the
immunosuppression caused by ultraviolet radiation-B (2, 22). In
addition, green tea polyphenols have shown protection against cytokines
induced by tumors (23).
MECHANISMS OF BIOLOGICAL EFFECTS OF TEA
Because tea consumption has been shown to
have protective effects against a variety of diseases, defining
the mechanisms of the biological effects of tea is important. In
addition, elucidation of mechanisms may provide additional opportunities
to intervene at other targets. Initial mechanistic studies (reviewed
in reference 2) regarding the cancer chemopreventive effects of
green tea or its polyphenols largely focused on:
1) protection against mutagenicity and genotoxicity
2) inhibition of biochemical markers of
3) inhibition of biochemical markers of
4) effects on detoxification enzymes,
5) trapping of activated metabolites of
6) antioxidant and free radical scavenging
activity. Novel mechanistic work to define the anticarcinogenic
effects of polyphenolic extracts from green tea and its constituents
has been pursued; recent advances in this area are described in
the following sections.
Green tea activates mitogen-activated protein kinases
The activation of mitogen-activated protein
kinases by green tea polyphenols was shown to be a potential signaling
pathway in the regulation of phase II enzyme gene expression mediated
by an antioxidant-responsive element (24). In this study, green
tea polyphenols induced chloramphenicol acetyltransferase (CAT)
activity in human hepatoma HepG2 cells transfected with a plasmid
construct containing an antioxidant-responsive element and a minimal
glutathione S-transferase Ya promoter linked to the CAT reporter
gene. This result indicates that green tea polyphenols stimulate
the transcription of phase II detoxifying enzymes through the antioxidant-responsive
element. In addition, green tea polyphenol treatment of HepG2 cells
resulted in a significant activation of extracellular signal–regulated
kinase 2 and c-Jun N-terminal kinase 1, which are members of the
mitogen-activated protein kinase family. Green tea polyphenol treatment
also increased messenger RNA amounts of the immediate-early genes
c-jun and c-fos.
EGCG inhibits urokinase activity
A widely publicized study showed that the
anticancer activity of EGCG in green tea might be due to inhibition
of the enzyme urokinase (u-plasminogen activator), one of the most
frequently expressed enzymes in human cancers (25). With the use
of molecular modeling, the authors showed that EGCG binds to urokinase,
blocking His 57 and Ser 195 of the urokinase catalytic triad and
extending toward Arg 35 from a positively charged loop of urokinase.
This computer-based calculation was verified by quantifying the
inhibition of urokinase activity with a spectrophotometric amidolytic
assay. The validity of this finding has been challenged, however
Green tea induces apoptosis and cell cycle arrest
In recent years, apoptosis has become a
challenging area of biomedical research. The life spans of both
normal and cancer cells within living systems are thought to be
significantly affected by the rate of apoptosis, a programmed type
of cell death that differs from necrotic cell death and is regarded
as a normal process of cell elimination (27). It follows that the
chemopreventive agents that can modulate apoptosis and thereby affect
the steady state cell population may be useful in the management
and therapy of cancer.
Many cancer-chemopreventive agents induce
apoptosis and, conversely, several tumor promoters inhibit apoptosis
(28–30). It is reasonable, therefore, to assume that chemopreventive
agents that have proven effects in animal tumor bioassay systems
or human epidemiologic studies on the one hand and that induce apoptosis
of cancer cells on the other hand may have wider implications for
the management of cancer. Only a few chemopreventive agents are
known to cause apoptosis, however (31).
We found that EGCG induced apoptosis and
cell cycle arrest in human epidermoid carcinoma cells A431 (32).
Importantly, we also found that the apoptotic response of EGCG was
specific to cancer cells, because the induction of apoptosis was
also observed in human carcinoma keratinocytes HaCaT, human prostate
carcinoma cells DU145, and mouse lymphoma cells LY-R but not in
normal human epidermal keratinocytes.
EGCG suppresses extracellular signals and
cell proliferation through epidermal growth factor receptor binding
Liang et al (33) showed that EGCG could
significantly inhibit DNA synthesis in A431 cells. In addition,
EGCG inhibited the protein tyrosine kinase activities of epidermal
growth factor (EGF) receptor, platelet-derived growth factor receptor,
and fibroblast growth factor receptor but not of pp60v-src, protein
kinase C, and protein kinase A. EGCG also inhibited the phosphorylation
of EGF receptor by EGF and blocked the binding of EGF to its receptor.
These findings suggest that EGCG might inhibit the process of tumor
formation by blocking cellular signal transduction pathways.
EGCG blocks induction of nitric oxide synthase
by down-regulating transcription factor nuclear factor B
Lin and Lin (34) assessed the effects of
EGCG on nitric oxide production by murine peritoneal macrophages.
Their results suggest that EGCG blocked early events of nitric oxide
synthase induction by inhibiting the binding of transcription factor
nuclear factor B to the inducible nitric oxide synthase (iNOS) promoter,
thereby inhibiting the induction of iNOS transcription.
EGCG and theaflavins inhibit tumor promoter-induced
activator protein 1 activation and cell transformation
To examine antitumor promotion effects of
EGCG and theaflavins at the molecular level, Dong et al (35) used
a JB6 mouse epidermal cell line, a system that has been used extensively
as an in vitro model for tumor promotion studies. EGCG and theaflavins
inhibited EGF- or 12-O-tetradecanoyl-phorbol-13-acetate–induced
cell transformation in a dose-dependent manner. EGCG and theaflavins
also inhibited activator protein 1 (AP-1)-dependent transcriptional
activity and DNA binding activity. Finally, this study showed that
the inhibition of AP-1 activation occurs through the inhibition
of a pathway dependent on c-Jun N-terminal kinase.
TEA AND CLINICAL TRIALS
Because epidemiologic studies and research
findings in laboratory animals have shown the chemopreventive potential
of tea polyphenols in cancer, the usefulness of these polyphenols
for humans should be evaluated in clinical trials. The first such
trial is being conducted by the MD Anderson Cancer Center in collaboration
with the Memorial Sloan-Kettering Cancer Center; MD Anderson has
obtained an Investigational New Drug application permit from the
US Food and Drug Administration to begin phase 1 clinical trials.
To examine the safety and possible efficacy of consuming the equivalent
of >10 cups (>2.4 L) of green tea/d, 30 cancer patients with
advanced solid tumors will be given daily green tea for >6 months.
CONCLUSION AND FUTURE DIRECTIONS
Dietary habits influence the risk of developing
a variety of diseases, especially cancer and heart disease. The
use of dietary substances is receiving increasing attention as a
practical approach for reducing the risk of developing these diseases.
Epidemiologic observations and laboratory studies have indicated
that tea consumption may have beneficial effects in reducing certain
types of cancer in some populations. Although a considerable body
of information provides evidence supporting the preventive potential
of tea against cancer, a proper understanding of the mechanisms
by which tea polyphenols reduce the risk of diseases is necessary
to devise strategies for better health. Black tea is the major form
of tea consumed, but its chemistry, biological activities, and chemopreventive
properties, especially of the polyphenols that are present, are
not well defined.
Because information on the bioavailability
of tea polyphenols after tea consumption is limited in humans, studies
on absorption, distribution, and metabolism of green and black tea
polyphenols in animals and humans are needed. After careful evaluation
of the available data and additional studies, specific recommendations
may be made for consumption of tea by humans. The usefulness of
tea polyphenols may be extended by combining them with other consumer
products, such as food items and vitamin supplements. This "designer-item"
approach may be useful for the human population.
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Gupta S, et al, Proc
Nat Acad Sci, 98(18), 2001
Green tea, a popular beverage consumed worldwide, has been shown
to possess cancer chemopreventive effects in a wide range of target
organs in rodent carcinogenesis models. The chemopreventive effects
of green tea against tumorigenesis and tumor growth have been attributed
to the biochemical and pharmacological activities of its polyphenolic
constituents. Epidemiological studies, although inconclusive, suggest
a protective effect of tea consumption on some cancer types in humans.
Limited epidemiological studies indicate that people who consume
tea regularly may have a lower risk of cancer of the prostate (CaP).
Further, the Japanese and Chinese populations who regularly consume
tea, especially green tea, have one of the lowest incidences of
CaP in the world. In addition, the incidence of CaP is also low
in other Asian men, who consume a traditional low-fat diet and tea.
Development of effective chemopreventive
agents against prostate cancer (CaP) for humans requires conclusive
evidence of their efficacy in animal models that closely emulates
human disease. The autochthonous transgenic adenocarcinoma of the
mouse prostate (TRAMP) model, which spontaneously develops metastatic
CaP, is one such model that mimics progressive forms of human disease.
Employing male TRAMP mice, we show that oral infusion of a polyphenolic
fraction isolated from green tea (GTP) at a human achievable dose
(equivalent to six cups of green tea per day) significantly inhibits
prostate cancer development and increases survival in these mice.
In two separate experiments, the cumulative
incidence of palpable tumors in untreated mice was 100%. In these
95%, 65%, 40%), and 25% exhibited distant site metastases to lymph
nodes, lungs, liver, and bone, respectively. However, green tea
polyphenols (GTP) resulted in (i) significant delay in primary tumor
incidence and tumor burden, (ii) significant decrease in prostate
(64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition
in serum insulin-like growth factor-I and restoration of insulin-like
growth factor binding protein-3 levels, and (iv) marked reduction
in the protein expression of proliferating cell nuclear antigen
(PCNA) in the prostate.
The striking observation of this study was
that green tea polyphenol (GTP) infusion resulted in almost complete
inhibition of distant site metastases. Furthermore, GTP consumption
caused significant apoptosis of prostate cancer (CaP) cells, which
possibly resulted in reduced dissemination of cancer cells, thereby
causing inhibition of prostate cancer development, progression,
and metastasis of CaP to distant organ sites.
In the present study, we determined the
consequence of oral infusion of a polyphenolic fraction from green
tea (GTP) on prostate cancer (CaP) development and progression at
a human-achievable dose. Results demonstrate that oral infusion
of GTP causes a significant inhibition in the development, progression,
and metastasis of CaP to distant organ sites. GTP was found to result
in significant prevention or delay (44% inhibition) in prostate
cancer development. GTP did not exhibit any symptoms of toxicity
or apparent signs of ill health. GTP infusion resulted in complete
absence of hyperplasia in the genitourinary (GU) apparatus, especially
in the seminal vesicles.
Because green tea is known to induce selective
apoptosis in cancer cells, we hypothesized that the observed inhibition
of prostate tumorigenesis by GTP infusion is mediated by increased
apoptosis of cancerous cells. To test our hypothesis, we used multiple
approaches of apoptosis determination. A significant increase in
apoptotic index (2.12 6 0.1 vs. 27.7 6 3.2% control vs. GTP) was
Extended tumor-free survival and survival
probability is the most desirable effect of any chemo-prevention
regimen. Therefore, in the next series of experiments, we evaluated
whether or not green tea polyphenol (GTP) infusion leads to tumor-free
survival and prolongs life expectancy. Our data indicated that GTP
resulted in the prolongation of lifespan and significantly increased
the tumor-free survival inasmuch as 50% remain tumor-free. In addition,
GTP exhibited a significant increase (70% higher) in life expectancy.
Because prostate cancer is typically diagnosed
in men aged 50 years and older, even a slight delay in the onset
and subsequent progression of the disease through the use of chemopreventive
agent(s) could have important health benefits. The most notable
implication of our work is that oral infusion of a human-achievable
dose of green tea results in significant inhibition in development
and progression of prostate cancer along with increased survival
in an animal model that emulates human disease. These data, therefore,
suggest that green tea consumption may have inhibitory effects on
prostate carcinogenesis in humans.
A number of studies have shown the growth-inhibitory
effects of green tea against many animal tumor bioassay systems
(Katiyar S, et al, Cancer Res, 52,
6890–6897, 1992), (Katiyar S, et al, Carcinogenesis, 14, 849–855,
1993), (Lu Y, et al, Carcinogenesis, 18, 2163–2169, 1997),
(Landau J, et al, Carcinogenesis 19, 501–507, 1998).
Recent laboratory studies have indicated that green tea and its
polyphenolic constituents impart inhibitory effects on the activities
of many enzymatic, metabolic, and signaling pathways that have relevance
to cancer development and progression
(Liao S & Hiipakka R, Biochem Biophys Res Commun, 214, 833–838,
1995), (Jankun J, et al., Nature, 387, 561, 1997), (Cao Y, &
Cao R, Nature, 398, 381, 1999), (Garbisa S,et al, Nat. Med, 5, 1216,
1999), (Nam S, et al, J Biol Chem, 276, 13322–13330, 2001),
(Menegazzi M, et al, FASEB J, 15, 1309–1311, 2001).
Studies have shown that polyphenols present
in green tea and caffeine possess cancer chemopreventive effects
(Huang M, et al, Cancer Res, 57, 2623–2629, 1997). Epidemiological
studies suggest a protective role of green tea against prostate
cancer development (Heilbrun L, et al, Br J Cancer 54, 677–683,
1986); (Kinlen L, et al, Br J Cancer 58, 397–401, 1988); (Katiyar
S, Mukhtar H, Int J Oncol, 8, 221–238, 1996); (Kohlmeier L,
et al, Nutr Cancer 27, 1–13, 1997); (Bushman J, Nutr Cancer,
31, 151–159, 1998). Cell culture studies have
shown that GTP inhibits growth of several types of human CaP cells
(Ahmad N, et al, J Natl Cancer Inst,
89, 1881–1886, 1997); (Yang G, et al, Carcinogenesis 19, 611–616,
1998); (Valcic S, et al, Anticancer Drugs 7, 461–468, 1996);
(Ahmad N, et al, J Natl Cancer Inst, 89, 1881–1886, 1997);
(Paschka A, et al, Cancer Lett 130, 1–7, 1998); (Gupta S,
et al, Toxicol Appl Pharmacol, 164, 82–90, 2000)
Studies indicate that 23% of prostate cancer
patients receiving surgical intervention still show evidence of
disease progression (Satariano W,
Cancer 83, 1180–1188. (52), (1998). Once the disease
becomes hormone refractory, treatment is palliative and median lifespan
is less than 12 months. Therefore, agents that may prolong the survival
and quality of life of such patients could have immediate clinical
importance. Studies from our laboratory have shown that green tea
polyphenols show promising testosterone-mediated cell growth inhibitory
effects in vitro as well as in vivo
(Gupta S, et al, Cancer Res. 59, 2115–2120, 1999).
In the present study, GTP infusion resulted in a significant increase
in tumor-free survival and survival probability. Based on these
results, we suggest that regular consumption of green tea may prolong
life expectancy and quality of life in prostate cancer patients.
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