Green Tea and Cancer: A Summary of the Evidence
Prepared by David Heber MD, PhD, FACP, FACN
April 23, 2003
Green tea consumption has been associated in population studies
reviewed below with a decreased risk of cancer in humans. This
evidence is particularly strong for gastric cancer, where studies
in China have demonstrated that both gastritis, the inflammatory
condition that precedes gastric cancer, and gastric cancer are
inversely associated with green tea intake ( Setiawan VW, Zhang
ZF, Yu GP, Lu QY, Li YL, Lu ML, Wang MR, Guo CH, Yu SZ, Kurtz
RC, Hsieh CC. Protective effect of green tea on the risks of
chronic gastritis and stomach cancer. Int J Cancer 2001;92:600-4).
Green tea consumption has also been associated with a reduced
risk of ovarian cancer ( Zhang M, Binns CW, Lee AH. Tea consumption
and ovarian cancer risk: a case-control study in China . Cancer
Epidemiol Biomarkers Prev 2002; 11:713-8). Green tea polyphenols
(GTPs) mainly consist of catechins (3-flavanols), of which (-)-epigallocatechin
gallate is the most abundant and the most extensively studied.
However, it is not the only active substance and studies from
our own lab have shown anti-cancer activities of the other related
compounds in green tea extracts. Green tea has been shown to
increase energy expenditure and be an adjunct to obesity treatments,
and obesity has been related to cancer risk in recent studies
from the American Cancer Society. One study in animals reviewed
below suggests that both the green tea catechins and caffeine
may reduce skin cancer by affecting the fat pads in the skin.
Recent observations have raised the possibility that green
tea catechins, in addition to their antioxidative properties,
also affect the molecular mechanisms involved in angiogenesis,
extracellular matrix degradation, regulation of cell death and
multidrug resistance. Green tea catechins affects these mechanism
each of which plays a crucial role in the development of cancer
in humans. These studies have been carried out in cell culture
by our group and others in several different models of cancer
in animals discussed below. The extraction of polyphenols from
green tea, as well as their bioavailability, are also known and
affect blood and tissue levels of the GTPs and consequently their
biological activities (Lee MJ, Maliakal P, Chen L, Meng X, Bondoc
FY, Prabhu S, Lambert G, Mohr S, Yang CS.Pharmacokinetics of
tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate
by humans: formation of different metabolites and individual
variability. Cancer Epidemiol Biomarkers Prev 2002;11:1025-32).
In addition, research on dietary GTPs as novel antiangiogenic
and antitumor compounds has also been conducted. These various
studies are summarized below in some detail. Non-supportive studies
are limited to a negative population study and one intervention
study in late stage advanced prostate cancer that was not hormone-responsive.
This is the most advanced stage of prostate cancer and it is
not surprising that green tea was not effective in this setting.
In fact, these patients were being treated with hormone antagonists
at the same time they were receiving green tea extract. The evidence
clearly shows that green tea catechins inhibit tumor growth directly
via suppressive actions on tumor cell mechanisms involved
in the multistep process of carcinogenesis and reduce tumor growth
in animal models of cancer. In addition, no tumor can grow to
more that 200 microns in diameter unless it grows its own blood
supply. This process, known as tumor angiogenesis, is at the
crux of an interaction between an invading tumor and the patient's
immune system. Green tea catechins have been clearly shown to
inhibit this key process in tumor growth in a number of studies
reviewed below including some from our research group at UCLA.
By inhibiting tumor angiogenesis, green tea catechins can tip
the balance in favor of the patient versus the tumor. Therefore,
while a minority of cancer patients die from their initial tumor,
it is far more common that an initial tumor is successfully treated
and that some years later the tumor recurs. When this recurrence
leads to spread of the tumor, a process known as metastasis,
it commonly leads to suffering and death. Green tea catechins,
by inhibiting new tumor blood vessel growth, could delay or prevent
tumor recurrence and this is the subject of several multimillion
dollar trials at various universities sponsored by the National
Cancer Institute. These trials involving patients with superficial
bladder cancer at UCLA and in skin cancer at the University of
Arizona would not have been undertaken without the significant
biological and scientific work reviewed here which establish
the likelihood that these trials will be successful. Therefore,
while there are no completed large clinical trials at this time
showing the benefits of green tea in preventing cancer , there
is a combination of strong evidence drawn from population studies,
animal studies and basic studies in cancer cells which establish
the biological and scientific basis for the claim that green
tea extract may reduce the risks of some forms of cancer.
1. Population-based Studies which are supportive.
Setiawan VW, Zhang ZF, Yu GP, Lu QY, Li YL, Lu ML, Wang
MR, Guo CH, Yu SZ, Kurtz RC, Hsieh CC. Protective effect of green
tea on the risks of chronic gastritis and stomach cancer. Int
J Cancer 2001 May 15;92(4):600-4
Despite the declining trend, stomach cancer remains
the second most common cancer worldwide. This study examined
the role of green tea consumption on chronic gastritis and stomach
cancer risks. A population-based case-control study was conducted
in Yangzhong , China , with 133 stomach cancer cases, 166 chronic
gastritis cases, and 433 healthy controls. Epidemiologic data
were collected by standard questionnaire and odds ratios (OR)
and 95% confidence intervals (CI) were estimated using logistic
regression models in SAS. Inverse association was observed between
green tea drinking and chronic gastritis and stomach cancer risks.
After adjusting for age, gender, education, body mass index,
pack-years of smoking and alcohol drinking, ORs of green tea
drinking were 0.52 (95% CI: 0.29-0.94) and 0.49 (95% CI: 0.31-0.77)
for stomach cancer and chronic gastritis, respectively. In addition,
dose-response relationships were observed with years of green
tea drinking in both diseases. The results provide further support
on the protective effect of green tea against stomach cancer.
This is the first time that green tea drinking was found to be
protective against chronic gastritis, which may be of importance
when designing intervention strategies for stomach cancer and
its pre-malignant lesions in the high-risk population.
Zhang M, Binns CW, Lee AH. Tea consumption and ovarian cancer
risk: a case-control study in China . Cancer Epidemiol Biomarkers
Prev 2002 Aug;11(8):713-8
To investigate whether tea consumption has an etiological
association with ovarian cancer, a case-control study was conducted
in China during 1999-2000. The cases were 254 patients with histologically
confirmed epithelial ovarian cancer. The 652 controls comprised
340 hospital visitors, 261 non-neoplasm hospital outpatients,
and 51 women recruited from the community. Information on the
frequency, type, and duration of tea consumption was collected
by personal interview using a validated questionnaire. The risk
of ovarian cancer for tea consumption was assessed using adjusted
odds ratios based on multivariate logistic regression analysis,
accounting for confounding demographic, lifestyle, and familial
factors including hormonal status and family ovarian cancer.
The ovarian cancer risk declined with increasing frequency and
duration of overall tea consumption. The adjusted odds ratio
was 0.39 for those drinking tea daily and 0.23 for those drinking
tea for >30 years, compared with nontea drinkers. The dose
response relationships were significant, and the inverse association
with ovarian cancer was observed for green tea consumption. This
study demonstrated that increasing frequency and duration of
tea drinking, especially green tea, can reduce the risk of ovarian
cancer.
2. Basic Studies Supporting the Anti-Cancer Effects of Green
Tea
Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert
G, Mohr S, Yang CS.Pharmacokinetics of tea catechins after ingestion
of green tea and (-)-epigallocatechin-3-gallate by humans: formation
of different metabolites and individual variability. Cancer Epidemiol
Biomarkers Prev 2002 Oct;11(10 Pt 1):1025-32
Green tea and tea polyphenols have been studied extensively
as cancer chemopreventive agents in recent years. The bioavailability
and metabolic fate of tea polyphenols in humans, however, are
not clearly understood. In this report, the pharmacokinetic parameters
of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin
(EGC), and (-)-epicatechin (EC) were analyzed after administration
of a single oral dose of green tea or decaffeinated green tea
(20 mg tea solids/kg) or EGCG (2 mg/kg) to eight subjects. The
plasma and urine levels of total EGCG, EGC, and EC (free plus
conjugated forms) were quantified by HPLC coupled to an electrochemical
detector. The plasma concentration time curves of the catechins
were fitted in a one-compartment model. The maximum plasma concentrations
of EGCG, EGC, and EC in the three repeated experiments with green
tea were 77.9 +/- 22.2, 223.4 +/- 35.2, and 124.03 +/- 7.86 ng/ml,
respectively, and the corresponding AUC values were 508.2 +/-
227, 945.4 +/- 438.4, and 529.5 +/- 244.4 ng x h x ml(-1), respectively.
The time needed to reach the peak concentrations was in the range
of 1.3-1.6 h. The elimination half-lives were 3.4 +/- 0.3, 1.7
+/- 0.4, and 2.0 +/- 0.4 h, respectively. Considerable interindividual
differences and variations between repeated experiments in the
pharmacokinetic parameters were noted. Significant differences
in these pharmacokinetic parameters were not observed when EGCG
was given in decaffeinated green tea or in pure form. In the
plasma, EGCG was mostly present in the free form, whereas EGC
and EC were mostly in the conjugated form. Over 90% of the total
urinary EGC and EC, almost all in the conjugated forms, were
excreted between 0 and 8 h. Substantial amounts of 4'-O-methyl
EGC, at levels higher than EGC, were detected in the urine and
plasma. The plasma level of 4'-O-methyl EGC peaked at 1.7 +/-
0.5 h with a half life of 4.4 +/- 1.1 h. Two ring-fission metabolites,
(-)-5-(3',4',5'-trihydroxyphenyl)-gamma-valerolactone (M4) and
(-)-5-(3',4'-dihydroxyphenyl)-valerolactone (M6), appeared in
significant amounts after 3 h and peaked at 8-15 h in the urine
as well as in the plasma. These results are useful for designing
the dose and dose frequency in intervention studies with tea
and for development of biomarkers of tea consumption. In addition
they demonstrate the bioavailability of a green tea extract supplement
or green tea in terms of supplying catechins in the blood stream.
This study makes the laboratory studies below relevant
since the catechins can be elevated by taking green tea or a
green tea extract supplement.
Wang YC, Bachrach U.The specific anti-cancer activity of green
tea (-)-epigallocatechin-3-gallate (EGCG). Amino Acids 2002;22(2):131-43
The effect of the green tea polyphenol-(-)epigallocatechin-3-gallate
(EGCG) was tested in cultures of normal and transformed NIH-pATM
ras fibroblasts. In this system transformation can be induced
at will by the addition of dexamethasone, which induces the expression
of H- ras by activating the mammary tumor virus long terminal
repeat (MMTV-LTR) promoter. This facilitates a reliable comparison
of the susceptibility of normal and transformed cells to EGCG.
It has been shown that EGCG inhibited the growth of transformed
but not of the normal fibroblasts. In an attempt to elucidate
the mode of the preferential inhibitory activity of EGCG, its
effect on growth promoting factors has been examined. The level
of ornithine decarboxylase (ODC, EC 4.1.1.17), which is a signal
for cellular proliferation, was reduced by EGCG in the transformed
but not in the normal cells. EGCG also showed strong inhibition
of tyrosine kinase and mitogen-activated protein kinase (MAPK)
activities, without affecting the kinases in the normal cells.
Similarly, EGCG also preferentially decreased the levels of the
oncogenes Ras and Jun in transformed cell. EGCG preferentially
induced apoptosis in the transformed fibroblasts. In vitro chemosensitivity
tests demonstrated that EGCG inhibited the proliferation of leukemic
cells. These findings establish the EGCG, a major green tea catechin,
can inhibit many of the key steps in the multistage process of
carcinogenesis within tumor cells. These studies establish the
basic biologic and scientific rationale for the actions of green
tea in inhibiting tumor growth at a cellular level.
Lu YP, Lou YR, Lin Y, Shih WJ, Huang MT, Yang CS, Conney AH.
Inhibitory effects of orally administered green tea, black tea,
and caffeine on skin carcinogenesis in mice previously treated
with ultraviolet B light (high-risk mice): relationship to decreased
tissue fat. Cancer Res 2001 Jul 1;61(13):5002-9
Treatment of SKH-1 hairless mice with ultraviolet B light
(UVB; 30 mJ/cm(2)) twice a week for 22 weeks resulted in tumor-free
animals with a high risk of developing malignant and nonmalignant
skin tumors during the next several months in the absence of
additional UVB treatment (high-risk mice). Oral administration
of green tea or black tea (6 mg tea solids/ml) to UVB-pretreated
high-risk SKH-1 mice for 23 weeks after stopping UVB treatment
decreased the number of tumors/mouse, decreased the size of the
parametrial fat pads, and decreased the thickness of the dermal
fat layer away from tumors and directly under tumors. Administration
of the decaffeinated teas had little or no effect on these parameters,
and adding caffeine (equivalent to the amount in the regular
teas) to the decaffeinated teas restored their inhibitory effects.
Administration of caffeine alone also decreased the number of
tumors/mouse, the size of the parametrial fat pads, and the thickness
of the dermal fat layer away from tumors and under tumors. Using
data from individual mice and linear regression and correlation
analysis, we found a highly significant positive correlation
between the thickness of the dermal fat layer away from tumors
and the number of tumors/mouse (r = 0.34; P = 0.0001), but the
correlation between average tumor size/mouse and the thickness
of the dermal fat layer away from tumors was weak (r = 0.16;
P = 0.034). The results suggested that p.o. administered tea
or caffeine may have decreased tumor multiplicity in part by
decreasing fat levels in the dermis. Additional analysis revealed
that oral administration of caffeinated beverages (green tea,
black tea, decaffeinated green tea plus caffeine, decaffeinated
black tea plus caffeine, or caffeine alone) decreased the thickness
of the dermal fat layer under large tumors to a much greater
extent than under small tumors. This is the first demonstration
of a close association between inhibition of carcinogenesis and
the lowering of tissue fat levels by a chemopreventive agent.
Afaq F, Adhami VM, Ahmad N, Mukhtar H. Inhibition of ultraviolet
B-mediated activation of nuclear factor kappaB in normal human
epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate.
Oncogene 2003 Feb 20;22(7):1035-44
Epigallocatechin-3-gallate (EGCG), the major constituent of
green tea, possesses significant anti-inflammatory and cancer
chemopreventive properties. Studies have shown the photochemopreventive
effects of green tea and EGCG in cell culture, animal models,
and human skin. The molecular mechanism(s) of photochemopreventive
effects of EGCG are incompletely understood. We recently showed
that EGCG treatment of the normal human epidermal keratinocytes
(NHEK) inhibits ultraviolet (UV)B-mediated activation of the
mitogen-activated protein kinase (MAPK) pathway. In this study,
we evaluated the effect of EGCG on UVB-mediated modulation of
the nuclear factor kappa B (NF-kappaB) pathway, which is known
to play a critical role in a variety of physiological functions
and is involved in inflammation and development of cancer. Immunoblot
analysis demonstrated that the treatment of NHEK with EGCG (10-40
microM) for 24 h resulted in a significant inhibition of UVB
(40 mJ/cm(2))-mediated degradation and phosphorylation of IkappaBalpha
and activation of IKKalpha, in a dose-dependent manner. UVB-mediated
degradation and phosphorylation of IkappaBalpha and activation
of IKKalpha was also observed in a time-dependent protocol (15
and 30 min, 1, 2, 3, 6, 12 h post-UVB exposure). Employing immunoblot
analysis, enzyme-linked immunosorbent assay, and gel shift assay,
we demonstrate that EGCG treatment of the cells resulted in a
significant dose- and time-dependent inhibition of UVB-mediated
activation and nuclear translocation of a NF-kappaB/p65. Our
data suggest that EGCG protects against the adverse effects of
UV radiation via modulations in NF-kappaB pathway, and provide
a molecular basis for the photochemopreventive effect of EGCG.
Zhang H, Spitz MR, Tomlinson GE, Schabath MB , Minna JD, Wu X.
Modification of lung cancer susceptibility by green tea extract
as measured by the comet assay. Cancer Detect Prev 2002;26(6):411-8
Green tea is known to possess various beneficial properties
that may affect carcinogen metabolism, free radical scavenging,
or formation of DNA adducts. Therefore, it is plausible that
green tea extract may modify BPDE-induced DNA damage. In this
report, the comet assay was used to (1) evaluate BPDE-induced
DNA damage as a potential marker of cancer susceptibility and
(2) assess the ability of green tea to modify BPDE-induced DNA
damage. DNA damage in individual comet cells was quantified by
(1) visually measuring the proportion of cells exhibiting migration
versus those without and (2) the length of damaged DNA migration
(comet tail). We detected a dose-response between BDPE concentration
and mean comet tail length in EBV-immortalized lymphoblastiod
(lymphoid) cell lines. As the concentration of BPDE increased
from 0.5 to 3 microM, the length of the mean comet tail length
increased proportionally in the 3590P (derived from a healthy
subject) and 3640P (derived from a patient with head and neck
cancer) cell lines. In separate experiments using lymphoid cells
from 21 lung cancer cases and 12 healthy subjects, the mean comet
tail length was significantly higher in the lung cancer cases
(80.19 +/- 15.55) versus the healthy subjects (59.94 +/- 14.23)
(P < 0.01). Similar findings were observed when analyzing
the mean percentage of comet induced cells (84.57 +/- 8.85 and
69.04 +/- 12.50, respectively) (P < 0.01). When green tea
extract was added in conjunction with BPDE, there was a notable
reduction of the mean comet tail length (13.29 +/- 0.97) as compared
to BPDE treatment alone (80.19 +/- 15.55) (P < 0.01) in lung
cancer cases. There were no statistical differences between the
baseline (no treatments) (12.74 +/- 0.63) and the green tea extract
treatment (13.06 +/- 0.97) (P = 0.21). These data suggest the
modification of lung cancer susceptibility by the green tea extract.
Similar results were observed for the percentage of induced comet
cells and the statistical trends were similar for the 12 healthy
subjects. This preliminary study demonstrated that the detection
of BPDE-induced DNA damage via the comet assay may be a useful
biologic marker of lung cancer susceptibility. The differential
effects in BPDE-induced DNA damage between lung cancer cases
and healthy subjects suggests predisposed cancer susceptibility
to lung cancer risk. This reports also demonstrated the chemopreventive
effects of green tea extract on BPDE-induced DNA damage. These
observations provide further support for the application of the
comet assay in molecular epidemiologic studies.
Li N, Chen X, Liao J, Yang G, Wang S, Josephson Y, Han C, Chen
J, Huang MT, Yang CS.Inhibition of 7,12-dimethylbenz[a]anthracene
(DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin.
Carcinogenesis 2002 Aug;23(8):1307-13
In this study, the effects of tea and curcumin on 7,12-dimethylbenz[a]anthracene
(DMBA)-induced oral carcinogenesis in hamsters were examined.
DMBA solution (0.5% in mineral oil, 0.1 ml) was applied topically
to the left cheek pouch of male Syrian golden hamsters 3 times/week
for 6 weeks. Two days after the last treatment of DMBA, the animals
received green tea (6 mg tea solids/ml) as drinking fluid, or
10 mmol curcumin applied topically 3 times/week, or the combination
of green tea and curcumin treatment, or no treatment for 18 weeks.
The combination of tea and curcumin significantly decreased the
oral visible tumor incidence from 92.3% (24/26) to 69.2% (18/26)
and the squamous cell carcinoma (SCC) incidence from 76.9% (20/26)
to 42.3% (11/26). The combination of tea and curcumin also decreased
the number of visible tumors and the tumor volume by 52.4 and
69.8%, as well as the numbers of SCC, dysplasic lesions and papillomas
by 62.0, 37.5 and 48.7%, respectively. Green tea or curcumin
treatment decreased the number of visible tumors by 35.1 or 39.6%,
the tumor volume by 41.6 or 61.3% and the number of SCC by 53.3
or 51.3%, respectively. Green tea also decreased the number of
dysplasic lesions. Curcumin also significantly decreased the
SCC incidence. Tea and curcumin, singly or in combination, decreased
the proliferation index in hyperplasia, dysplasia and papillomas.
Only the combination treatment decreased the proliferation index
in SCC. Tea alone and in combination with curcumin significantly
increased the apoptotic index in dysplasia and SCC. Curcumin,
alone and in combination with tea, significantly inhibited the
angiogenesis in papilloma and SCC. The results suggested that
green tea and curcumin had inhibitory effects against oral carcinogenesis
at the post-initiation stage and such inhibition may be related
to the suppression of cell proliferation, induction of apoptosis
and inhibition of angiogenesis.
Orner GA, Dashwood WM, Blum CA, Diaz GD, Li Q, Al-Fageeh M, Tebbutt
N, Heath JK, Ernst M, Dashwood RH. Response of Apc(min) and A33
(delta N beta-cat) mutant mice to treatment with tea, sulindac,
and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutat
Res 2002 Sep 30;506-507:121-7
This study compared the inhibitory effects of white
and green teas with sulindac, a nonsteroidal anti-inflammatory
agent, in two different mouse models of intestinal tumorigenesis.
In the Apc(min) mouse, white and green teas given at human-relevant
concentrations (1.5% w/v, 2-min brew), and sulindac (80 ppm in
the drinking water), each suppressed polyp formation by approximately
50%, and the combination of white tea plus sulindac was more
effective than either treatment alone (P=0.05). Mice expressing
an N-terminally truncated, oncogenic version of beta-catenin
(A 33(delta N beta-cat) mutant mice) developed colonic aberrant
crypt foci (ACF) spontaneously, but PhIP treatment increased
the incidence and number of ACF per colon. In the normal-looking
intestinal mucosa of Apc(min) and A 33(delta N beta-cat) mice,
white tea plus sulindac treatment markedly attenuated the expression
of beta-catenin protein, and this was recapitulated in vitro
in cells transiently transfected with beta-catenin plus Tcf-4
and treated with tea or the major tea polyphenol epigallocatechin-3-gallate
(EGCG). Expression of a beta-catenin/Tcf reporter was inhibited
by EGCG in the transfected cells, and the beta-catenin/Tcf target
genes cyclin D1 and c-jun were downregulated in vivo by tea plus
sulindac treatment. Collectively, the data support a chemopreventive
role for tea and sulindac against intermediate and late stages
of colon cancer, via effects on the beta-catenin/Tcf signaling
pathway.
Zhou JR, Yu L, Zhong Y, Blackburn GL Soy phytochemicals and tea
bioactive components synergistically inhibit androgen-sensitive
human prostate tumors in mice.J Nutr 2003 Feb;133(2):516-21
This study identified synergistic effects between soy and tea
components on prostate tumor progression in a mouse model of
orthotopic androgen-sensitive human prostate cancer. Soy phytochemical
concentrate (SPC), black tea and green tea were compared with
respect to tumorigenicity rate, primary tumor growth, tumor proliferation
index and microvessel density, serum androgen level and metastases
to lymph nodes. SPC, black tea and green tea significantly reduced
tumorigenicity. SPC and black tea also significantly reduced
final tumor weights. Green tea did not reduce final tumor weight,
although it tended to elevate (P = 0.14) the serum dihydrotestosterone
(DHT) concentration. The combination of SPC and black tea synergistically
inhibited prostate tumorigenicity, final tumor weight and metastases
to lymph nodes in vivo. The combination of SPC and green tea
synergistically inhibited final tumor weight and metastasis and
significantly reduced serum concentrations of both testosterone
and DHT in vivo. Inhibition of tumor progression was associated
with reduced tumor cell proliferation and tumor angiogenesis.
This study demonstrated activity of green tea in an animal model
where human prostate tumor tissue was implanted in the mouse
prostate. The study suggests green tea may be useful in prevention
of prostate tumor progression. However, similar effects of black
tea and soy protein as well as the interactions require further
research.
Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate-induced
cell cycle arrest and apoptosis of human prostate carcinoma cells.
Arch Biochem Biophys 2003 Feb 1;410(1):177-85
Epigallocatechin-3-gallate (EGCG), the major polyphenolic
constituent present in green tea, is a promising chemopreventive
agent. We recently showed that green tea polyphenols exert remarkable
preventive effects against prostate cancer in a mouse model and
many of these effects are mediated by the ability of polyphenols
to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA
98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1
phase cell cycle arrest and apoptosis of both androgen-sensitive
LNCaP and androgen-insensitive DU145 human prostate carcinoma
cells, irrespective of p53 status [Toxicol. Appl. Pharmacol.
164 (2000) 82]. Here, we provide molecular understanding of this
effect. We tested a hypothesis that EGCG-mediated cell cycle
dysregulation and apoptosis is mediated via modulation of cyclin
kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery.
As shown by immunoblot analysis, EGCG treatment of LNCaP and
DU145 cells resulted in significant dose- and time-dependent
(i) upregulation of the protein expression of WAF1/p21, KIP1/p27,
INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein
expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but
not of cyclin D2, (iii) increase in the binding of cyclin D1
toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding
of cyclin E toward cdk2. Taken together, our results suggest
that EGCG causes an induction of G1 phase ckis, which inhibits
the cyclin-cdk complexes operative in the G0/G1 phase of the
cell cycle, thereby causing an arrest, which may be an irreversible
process ultimately leading to apoptotic cell death. This is the
first systematic study showing the involvement of each component
of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest
and apoptosis of human prostate carcinoma cells by EGCG.
Yoo HG, Shin BA, Park JC, Kim HS, Kim WJ, Chay KO, Ahn BW,
Park RK, Ellis LM, Jung YD.Induction of apoptosis by the green
tea flavonol (-)-epigallocatechin-3-gallate in human endothelial
ECV 304 cells. Anticancer Res 2002 Nov-Dec;22(6A):3373-8
We have previously shown that treatment with (-)-epigallocatechin-3-gallate
(EGCG) inhibited vascularity and tumor growth in human colon
cancer xenografts in nude mice (Jung et al: Br J Cancer 84, 2001).
In this study, we examined whether endothelial cell death by
EGCG is mediated by apoptosis and which molecular mechanisms
are involved in this process. EGCG was found to suppress cell
growth and induce apoptosis largely through mitochondrial depolarization,
activation of caspase-3 and cleavage of DNA fragmentation factor-45
in human endothelial ECV 304 cells. The induction of apoptosis
by EGCG was confirmed by cleaved and condensed nuclear chromatin
and DNA hypoploidy. These results suggest that EGCG may exert
at least part of its anticancer effect by inhibiting angiogenesis
through inducing endothelial apoptosis.
Vergote D, Cren-Olive C, Chopin V, Toillon RA, Rolando C,
Hondermarck H, Le Bourhis X. (-)-Epigallocatechin (EGC) of green
tea induces apoptosis of human breast cancer cells but not of
their normal counterparts. Breast Cancer Res Treat 2002 Dec;76(3):195-201
(-)-Epigallocatechin (EGC), one of green tea polyphenols,
has been shown to inhibit growth of cancer cells. However its
mechanism of action is poorly known. We show here that EGC strongly
inhibited the growth of breast cancer cell lines (MCF-7 and MDA-MB-231)
but not that of normal breast epithelial cells. The inhibition
of breast cancer cell growth was due to an induction of apoptosis,
without any change in cell cycle progression. MCF-7 cells are
known to express a wild-type p53 whereas MDA-MB-231 cells express
a mutated p53. The fact that EGC induced apoptosis in both these
cell lines suggests that the EGC-triggered apoptosis is independent
of p53 status. Moreover, neutralizing antibodies against the
death receptor Fas and inhibitors of caspases, such as caspase-8
and -10, efficiently inhibited the EGC-triggered apoptosis. In
addition, immunoblotting revealed that EGC treatment was correlated
with a decrease in Bcl-2 and an increase in Bax level. These
results suggest that EGC-triggered apoptosis in breast cancer
cells requires Fas signaling.
Sartippour MR, Heber D, Ma J, Lu Q, Go VL, Nguyen M.
Green tea and its catechins inhibit breast cancer xenografts.
Nutr Cancer 2001;40(2):149-56
It is widely accepted that the main active component of green
tea is epigallocatechin-3-gallate (EGCG). In this study, we examined
the effect of green tea extracts on breast cancer growth and
endothelial cells in in vitro assays and in animal models. Furthermore,
we compared the potency of the different catechin components
of green tea extract (GTE), including EGCG. Our data showed that
mixed GTE and its individual catechin components were effective
in inhibiting breast cancer and endothelial cell proliferation.
In mouse experiments, GTE suppressed xenograft size and decreased
the tumor vessel density.
These results demonstrated the value of all catechins and
argue for the use of a mixed GTE as a botanical dietary supplement,
rather than purified EGCG, in future clinical trials.
Sartippour MR, Heber D, Zhang L, Beatty P, Elashoff D, Elashoff
R, Go VL, Brooks MN. Inhibition of fibroblast growth factors
by green tea. Int J Oncol 2002 Sep;21(3):487-91
In a previous study, the effect of green tea on breast cancer
growth and endothelial cells both in in vitro assays and in animal
models was studied. The data show that both mixed green tea extract
(GTE) as well as its individual catechin components are effective
in inhibiting breast cancer and endothelial cell proliferation
in vitro, and that GTE suppresses breast cancer xenograft size
and decreases the tumor blood vessel density in vivo. In the
present study, further results demonstrate that 40 microg/ml
GTE or EGCG can decrease the levels of the angiogenic factor
bFGF (basic fibroblast growth factor) levels in the cells. This
phenomenon is observed in both human umbilical vein endothelial
cells (HUVECs) and in human breast cancer cells MDA-MB231. This
effect is dose dependent. Furthermore, GTE and EGCG decrease
the transcript levels of bFGF and aFGF (acidic fibroblast growth
factor) in HUVECs and MDA-MB231 cells. Our findings suggest that
the inhibition of the angiogenic fibroblast growth factors could
account for one of the mechanisms of green tea's actions. Since
cancer is angiogenesis dependent, this may partially explain
the antineoplastic effects associated with green tea consumption.
Sartippour MR, Shao ZM, Heber D, Beatty P, Zhang L, Liu C, Ellis
L, Liu W, Go VL, Brooks MN. Green tea inhibits vascular endothelial
growth factor (VEGF) induction in human breast cancer cells.
J Nutr 2002 Aug;132(8):2307-11
A previous study showed that green tea extract (GTE) as well
as its individual catechin components inhibited MDA-MB231 breast
cancer cell and human umbilical vein endothelial cell (HUVEC)
proliferation. Further, GTE suppressed breast cancer xenograft
size and decreased the tumor vessel density in vivo. In the current
study, the effect of GTE on the major angiogenic factor vascular
endothelial growth factor (VEGF) was examined in an in vitro
experiment. GTE or EGCG (40 mg/L) significantly decreased the
levels of the VEGF peptide secreted into conditioned media. This
occurred in both HUVEC and human breast cancer cells and the
effect was dose dependent. Furthermore, GTE and EGCG decreased
the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred
at the transcriptional regulation level and was accompanied by
a significant decrease in VEGF promoter activity. The experiments
also showed that GTE decreased c-fos and c-jun RNA transcripts,
suggesting that activator protein (AP)-1-responsive regions present
in the human VEGF promoter may be involved in the inhibitory
effect of GTE. Furthermore, GTE suppressed the expression of
protein kinase C, another VEGF transcription modulator, in breast
cancer cells. Inhibition of VEGF transcription appeared to be
one of the molecular mechanism(s) involved in the antiangiogenic
effects of green tea, which may contribute to its potential use
for breast cancer treatment and/or prevention.
3. Non- Supportive Studies
Tsubono Y, Nishino Y, Komatsu S, Hsieh CC, Kanemura S, Tsuji
I, Nakatsuka H, Fukao A, Satoh H, Hisamichi S. Green tea and
the risk of gastric cancer in Japan. N Engl J Med 2001 Mar 1;344(9):632-6
In January 1984, a total of 26,311 residents in three
municipalities of Miyagi Prefecture , in northern Japan (11,902
men and 14,409 women 40 years of age or older), completed a self-administered
questionnaire that included questions about the frequency of
consumption of green tea. During 199,748 person-years of follow-up,
through December 1992, 419 cases of gastric cancer were identified
(in 296 men and 123 women). Cox regression was used to estimate
the relative risk of gastric cancer according to the consumption
of green tea. In this study, green-tea consumption was not associated
with the risk of gastric cancer. After adjustment for sex, age,
presence or absence of a history of peptic ulcer smoking status,
alcohol consumption, other dietary elements, and type of health
insurance, the relative risks associated with drinking one or
two, three or four, and five or more cups of green tea per day,
as compared with less than one cup per day, were 1.1 (95 percent
confidence interval, 0.8 to 1.6), 1.0 (95 percent confidence
interval, 0.7 to 1.4), and 1.2 (95 percent confidence interval,
0.9 to 1.6), respectively (P for trend=0.13). The results were
similar after the 117 cases of gastric cancer that were diagnosed
in the first three years of follow-up had been excluded, with
respective relative risks of 1.2 (95 percent confidence interval,
0.8 to 1.8) 1.0 (95 percent confidence interval, 0.7 to 1.5),
and 1.4 (95 percent confidence interval, 1.0 to 1.9) (P for trend=0.07).
In this population-based prospective cohort study in Japan ,
there was no association between green-tea consumption and the
risk of gastric cancer.
While the nearly 200,000 patient years of follow-up sounds
impressive in the above study, when one divides this number by
the over 26,000 participants, it amounts to less than 8 years
of follow-up on average. As indicated in the attempt of these
investigators to adjust for potentially confounding factors,
smoking and alcohol intake are major causative factors in Japan
of gastric cancer. Green tea catechins have their major effects
on gastritis and progression to cancer as shown in the study
by Zhang et al. Therefore, it is not surprising that a study
with a relatively short period of study of less than 8 years
on average would fail to find an association. Furthermore, some
individuals were excluded from a subsequent analysis who apparently
already had gastric cancer at the time of entry into the study.
Excluding these individuals helped the analysis in one way by
removing a confounding factor (the presence of a cancer). However,
this exclusion markedly reduced the power of the study by reducing
the number of cases detected during the follow-up period of
less than 8 years from 419 to 302 cases. Therefore, this study
may have easily missed an association between green tea consumption
and gastric cancer.
Ohno Y, Yoshimura T; Japan Collaborative Cohort Study Group.
A prospective study of stomach cancer death in relation to green
tea consumption in Japan . Br J Cancer 2002 Jul 29;87(3):309-13
To evaluate whether green tea consumption provides protection
against stomach cancer death, relative risks were calculated
using Cox proportional hazards regression analysis in the Japan
Collaborative Study for Evaluation of Cancer Risk, sponsored
by the Ministry of Health and Welfare (JACC Study). The study
was based on 30 370 men and 42 481 women aged 40-79. After adjustment
for age, smoking status, history of peptic ulcer, family history
of stomach cancer along with certain dietary items, the risks
associated with drinking one or two, three or four, five to nine,
and 10 or more cups of green tea per day, relative to those of
drinking less than one cup per day, were 1.6 (95% CI: 0.9-2.9),
1.1 (95% CI: 0.6-1.9), 1.0 (95% CI: 0.5-2.0), and 1.0 (95% CI:
0.5-2.0), respectively, in men (P for trend=0.669), and 1.1 (95%
CI: 0.5-2.5), 1.0 (95% CI: 0.5-2.5), 0.8 (95% CI: 0.4-1.6), and
0.8 (95% CI: 0.3-2.1), respectively, in women (P for trend=0.488).
No inverse association between green tea consumption and the
risk of stomach cancer death was found in this study.
This study is was designed as a case-control study. These types
of population studies by comparing characteristics of those diagnosed
with cancer to controls studied at the same regardless of the
numbers of participants can miss associations which are detected
in long-term follow-up of the same populations over decades.
The latter studies are called cohort studies and represent a
higher standard of proof in population-based cancer epidemiology.
Factors at the time of diagnosis including poor memory
of dietary intake, metabolic effects of the tumor on metabolism,
and other changes secondary to the presence of the tumor can
confound studies designed as case-control comparisons. While
positive findings in such a study would be supportive, the finding
of no association is not proof of the absence of any relationship
and does not contradict the supportive studies from China reviewed
above which have much more biological information relevant to
the prevention of gastric cancer including information on the
protective role of green tea in chronic gastritis which is a
pre-malignant lesion in a high-risk population.
Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P,
Tan W, Fitch TR, Rowland KM, Young CY, Flynn PJ. A phase II trial
of green tea in the treatment of patients with androgen independent
metastatic prostate carcinoma. Cancer 2003 Mar 15;97(6):1442-6
Recent laboratory and epidemiologic studies have suggested
that green tea has antitumor effects in patients with prostate
carcinoma. This Phase II trial explored green tea's antineoplastic
effects in patients with androgen independent prostate carcinoma.
This study, which was conducted by the North Central Cancer Treatment
Group, evaluated 42 patients who were asymptomatic and had manifested,
progressive prostate specific antigen (PSA) elevation with hormone
therapy. Continued use of luteinizing hormone-releasing hormone
agonist was permitted; however, patients were ineligible if they
had received other treatments for their disease in the preceding
4 weeks or if they had received a long-acting antiandrogen therapy
in the preceding 6 weeks. Patients were instructed to take 6
grams of green tea per day orally in 6 divided doses. Each dose
contained 100 calories and 46 mg of caffeine. Patients were monitored
monthly for response and toxicity. Tumor response, defined as
a decline >/= 50% in the baseline PSA value, occurred in a
single patient, or 2% of the cohort (95% confidence interval,
1-14%). This one response was not sustained beyond 2 months.
At the end of the first month, the median change in the PSA value
from baseline for the cohort increased by 43%. Green tea toxicity,
usually Grade 1 or 2, occurred in 69% of patients and included
nausea, emesis, insomnia, fatigue, diarrhea, abdominal pain,
and confusion. However, six episodes of Grade 3 toxicity and
one episode of Grade 4 toxicity also occurred, with the latter
manifesting as severe confusion.
This study concluded that green tea has limited anticancer activity,
as defined by a decline in PSA levels, among patients with androgen
independent prostate carcinoma. This is the most advanced stage
of prostate cancer and it is not surprising that green tea was
not effective in this setting. In fact, these patients were being
treated with hormone antagonists, which are the last option prior
to chemotherapy in prostate cancer treatment and follows primary
treatment and recurrence of the tumor as judged by a rising PSA
level in most applications of this agent. ( Heber, D., The Leuprolide
Study Group (1 of 22 authors). Leuprolide Versus Diethylstilbestrol
for Metastatic Prostate Cancer. New Eng. J. Med., 311:1281-1286,
1984). at the same time they were receiving green tea extract.
The hormone antagonists are so effective that when failure occurs
it is not surprising that green tea extract was not effective
in stopping the advancement of tumor cells that had developed
resistance both to androgens(male hormones which stimulate the
growth of early prostate cancer) and to this antagonist treatment.
The evidence from a number of studies reviewed above clearly
shows that green tea catechins inhibit tumor growth directly
via suppressive actions on tumor cell mechanisms involved in
the multistep process of carcinogenesis and reduce tumor growth
in animal models of cancer. In addition, no tumor can grow to
more that 200 microns in diameter unless it grows its own blood
supply. This process, known as tumor angiogenesis, is at the
crux of an interaction between an invading tumor and the patient's
immune system. Green tea catechins have been clearly shown to
inhibit this key process in tumor growth in a number of studies
reviewed below including some from our research group at UCLA.
By inhibiting tumor angiogenesis, green tea catechins can tip
the balance in favor of the patient versus the tumor. Therefore,
while a minority of cancer patients die from their initial tumor,
it is far more common that an initial tumor is successfully treated
and that some years later the tumor recurs. When this recurrence
leads to spread of the tumor, a process known as metastasis,
it commonly leads to suffering and death. This is not the time
when you would use a preventive agent such as green tea. This
study is an example of an unfortunate trend of studies being
designed to disprove the utility of dietary supplements by placing
them in situations where they cannot be effective and publishing
the results. A celebrated example of this was the well-publicized
trial of St.John's wort in major depression published in the
prestigious Journal of the American Medical Association.
( Hypericum Depression Trial Study Group .Effect of Hypericum
perforatum ( St John's wort) in major depressive disorder: a
randomized controlled trial. JAMA 2002 Apr 10;287(14):1807-14).
St. John's wort is intended for the treatment of mood disorders
and mild depression, and was never intended to treat major depression
which is resistant to the most active antidepressant drugs. In
fact, sertraline (Serzone) was included as a positive control.
Neither the results from sertraline nor St.John's wort were different
from placebo. However, the conclusion drawn both in the abstract
and the publicity which followed was that St. John's wort was
ineffective for depression. The above trial green tea in advanced
prostate cancer represents a parallel example of this type of
negative interpretation of a study. In this instance, there was
progression of advanced stage prostate cancer in the presence
of green tea extract used in addition to a very potent hormone
blockade. If green tea is to be effective in prostate cancer,
it would need to be used to reduce the risk of prostate cancer
in healthy men or to reduce the recurrence risk of prostate cancer
immediately after initial treatment with surgery or radiation.
Testing green tea in advanced prostate cancer has no bearing
on its application in prostate cancer prevention.
Conclusion
In sum, based on all of the publicly available scientific evidence,
I conclude that significant and credible scientific evidence
supports the conclusion that:
* Some scientific evidence suggests that consumption of green
tea may reduce the risk of gastric cancer.
* Some scientific evidence suggests that consumption of green
tea extract may reduce the risk of gastric cancer.
* Some scientific evidence suggests that consumption of green
tea may reduce the risk of certain forms of cancer.
* Some scientific evidence suggests that consumption of green
tea extract may reduce the risk of certain form of cancer.
Respectfully submitted,
________________________
David Heber, M.D., Ph.D.
* Setiawan VW, et al. Protective effect of green tea
on the risks of chronic gastritis and stomach cancer. Int J Cancer
2001 May 15; 92(4): 600-4.
* Zhang M, et al. Tea consumption and ovarian cancer risk:
a case-control study in China . Cancer Epidemiol Biomarkers Prev
2002 Aug; 11(8): 713-8.
* Lee MJ, et al. Pharmacokinetics of tea catechins after
ingestion of green tea and (-)-epigallocatechin-3-gallate by
humans: formation of different metabolites and individual variability.
Cancer Epidemiol Biomarkers Prev 2002 Oct; 11(10 Pt 1): 1025-32.
* Wang YC, et al. The specific anti-cancer activity of
green tea (-)-epigallocatechin-3-gallate (EGCG). Amino Acids
2002; 22(2): 131-43.
* Lu YP, et al. Inhibitory effects of orally administered
green tea, black tea, and caffeine on skin carcinogenesis in
mice previously treated with ultraviolet B light (high-risk mice):
relationship to decreased tissue fat. Cancer Res 2001 Jul 1;
61(13): 5002-9.
* Afaq F, et al. Inhibition of ultraviolet B-mediated
activation of nuclear factor kappaB in normal human epidermal
keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate.
Oncogene 2003 Feb 20; 22(7): 1035-44.
* Zhang H, et al. Modification of lung cancer susceptibility
by green tea extract as measured by the comet assay. Cancer Detect
Prev 2002; 26(6): 411-8.
* Li N, et al. Inhibition of 7,12-dimethylbenz[a]anthracene
(DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin.
Carcinogenesis 2002 Aug; 23(8): 1307-13.
* Orner GA , et al. Response of Apc(min) and A33 (delta
N beta-cat) mutant mice to treatment with tea, sulindac, and
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutat
Res 2002 Sep 30; 506-507: 121-7.
* Zhou JR, et al. Soy phytochemicals and tea bioactive
components synergistically inhibit androgen-sensitive human prostate
tumors in mice.J Nutr 2003 Feb; 133(2): 516-21.
* Gupta S, et al. Molecular pathway for (-)-epigallocatechin-3-gallate-induced
cell cycle arrest and apoptosis of human prostate carcinoma cells.
Arch Biochem Biophys 2003 Feb 1; 410(1): 177-85.
* Yoo HG, et al. Induction of apoptosis by the green tea
flavonol (-)-epigallocatechin-3-gallate in human endothelial
ECV 304 cells. Anticancer Res 2002 Nov-Dec; 22(6A): 3373-8.
* Vergote D, et al. Epigallocatechin (EGC) of green tea
induces apoptosis of human breast cancer cells but not of their
normal counterparts. Breast Cancer Res Treat 2002 Dec; 76(3):
195-201.
* Sartippour MR, et al. Green tea and its catechins inhibit
breast cancer xenografts. Nutr Cancer 2001; 40(2): 149-56.
* Sartippour MR, et al. Inhibition of fibroblast growth
factors by green tea. Int J Oncol 2002 Sep; 21(3): 487-91.
* Sartippour MR, et al. Green tea inhibits vascular endothelial
growth factor (VEGF) induction in human breast cancer cells.
J Nutr 2002 Aug; 132(8): 2307-11.
* Tsubono Y, et al. Green tea and the risk of gastric
cancer in Japan . N Engl J Med 2001 Mar 1; 344(9): 632-6.
* Ohno Y, Yoshimura T; Japan Collaborative Cohort Study Group.
A prospective study of stomach cancer death in relation
to green tea consumption in Japan . Br J Cancer 2002 Jul 29 ;87(3):
309-13.
* Jatoi A, et al. A phase II trial of green tea in the
treatment of patients with androgen independent metastatic prostate
carcinoma. Cancer 2003 Mar 15; 97(6): 1442-6.
|
OPC-T - #20681 - 60 Capsules Wholesale Price: $28.95
Anti-oxidants are compounds that easily react
with oxygen protecting the cells from the damaging reactions
of the oxygen radical. OPC does more than protect, OPC helps
repair by improving and stabilizing the skin protein collagen
and improving the condition of arteries and capillaries.
OPC protects brain and nerve tissue because OPC penetrates the
blood-brain barrier. OPC enhances the wellness effects of vitamin
C and has been shown to be 20 times more effective than vitamin
C and 50 times more effective than vitamin E as an anti-oxidant.
The anti-oxidant OPC reduces tissue damage caused by free radicals.
OPC has been shown to help the body to improve circulation, resist
blood vessel and skin damage, mental deterioration, reduce inflammation
and other damage caused by harmful free radicals. OPC may relieve
the trauma and pain caused by arthritis, diabetes and stroke,
and is used for the prevention of cardiovascular diseases and
cancer because of its unique role as a potent anti-oxidant and
as a vita-min C "enhancer.
OPC prevents vitamin C from oxidizing to dehvdroascorbate. OPC
helps by its enzyme action, ascorbic oxidize, that metabolizes
the bodys vitamin C. OPC helps vitamin C by providing hydrogen
ions to reduce glutathione. Reduced glutathione converts oxidized
vitamin C (dehydroascorbate) to its active form (ascorbate).
Supplement Facts
- Serving Size: 1 Capsule |
|
Amount Per Serving |
% Daily Value |
Green Tea leaf |
100 mg |
Ý |
Grape seed |
50 mg |
Ý |
Ý Daily Value not established |
Other Ingredients: Gelatin capsule
(gelatin and water) |
Directions: Take 1 capsule, two
times a day, with meals. |
Wholesale
Price: $28.95
Case
(4 Bottles) $99.95
|