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Proc. Natl. Sci. Counc. ROC(B)
Vol. 24, No. 1, 2000. pp. 1-13
(Invited Review Paper)
Cancer Chemoprevention by Tea Polyphenols
J EN -K UN LIN AND Y U -C HIH LIANG
Institute of Biochemistry
College of Medicine
National Taiwan University
Taipei, Taiwan, R.O.C.
(Received March 12, 1999; Accepted May 4, 1999)
ABSTRACT
Tea is one of the most widely consumed beverages, second only to water. Many experimental
researches in laboratory animals demonstrated that tea components had an inhibitory effect on carcino-
genesis at a number of organ sites. The inhibitory effects of tea against carcinogenesis have been attrib-
uted to the biologic activities of the polyphenol fraction in tea. This review summarizes experimental
data on chemopreventive effects of tea polyphenols in various tumor bioassay systems. Many laboratory
studies have demonstrated the inhibitory effects of green tea polyphenols, especially (-)-epigallocate-
chin-3-gallate (EGCG), on carcinogenesis in animals models. The majority of these studies have been
conducted in mouse skin tumor models, where tea polyphenols were used either as oral feeding in
drinking water or in direct local application. Most studies used 12-O-tetradecanoylphorbol-13-acetate
(TPA) or ultraviolet (UV) radiation as the tumor promoter and found anticarcinogenic effects caused by
green tea polyphenols. Black tea was also found to be effective, although the activity was weaker than
that of green tea in some experiments. Other studies showed that black tea polyphenols-theaflavins
exhibited stronger anticarcinogenic activity than did EGCG. Caffeine in tea was also important for tea
to prevent tumorigenesis. The molecular mechanisms of the cancer chemopreventive effects of tea
polyphenols are not completely understood. They are most likely related to the mechanisms of bio-
chemical actions of tea polyphenols, which include antioxidative activities, modulation of xenobiotic
metabolite enzymes and inhibition of tumor promotion. In addition, we have also proposed that tea
polyphenols function as cancer chemopreventive agents through modulation of mitotic signal transduc-
tion. However, the molecular mechanisms involved in this modulation need further investigation.
Key Words: cancer chemoprevention, tea polyphenols, carcinogenesis, EGCG
I. Introduction of initiated cells into papillomas (Slaga et al., 1996).
These changes are believed to result from epigenetic
Epidemiological surveys and experimental studies mechanisms, such as ornithine decarboxylase (ODC),
have provided evidence that environmental factors, protein kinase C (PKC) and prostaglandins. (3) The
including dietary substances, play a major role in the process of tumor progression is characterized by a
development of cancer (ACS, 1995). The mechanisms high level of genetic instability that leads to a number
of carcinogenesis involve multiple stages of biochemi- of chromosomal alterations (Warren et al., 1993).
cal and molecular alterations in target cells. The Cancer chemoprevention can be defined as the
process of skin carcinogenesis involves the stepwise prevention, inhibition, or reversal of carcinogenesis by
accumulation of genetic changes, ultimately leading to administration of one or more chemical entities, either
malignancy (DiGiovanni, 1992; Slaga et al., 1995, as individual drugs or as naturally occurring con-
1996). There are three main steps: (1) The first step in stituents of the diet. Flavonoids are naturally occuring
multistage skin carcinogenesis is initiation, which low molecular weight polyphenolic compounds widely
involves carcinogen induced genetic changes. This distributed in fruits, vegetables and beverages. People
stage appears to be rapid and irreversible. It is pre- who eat diets rich in fruits and vegetables have lower
sumed to involve irreversible modification of DNA, incidences of diseases such as cancer (Ziegler, 1991).
perhaps resulting in one or more mutations (Garner, Numerous experimental studies have examined the role
1998). (2) A much slower stage of carcinogenesis is of specific flavonoids in disease prevention. For exam-
promotion, which is believed to involve selective and ple, increased flavonoid intake was associated with
sustained hyperplasia, leading to the specific expansion decreased risk of cardiovascular disease and carcino-
–1–
J.K. Lin and Y.C. Liang
1998a). Nonfermented green tea contains several
groups of polyphenols, which include flavanols, fla-
vanols and their glycosides, leucoanthocyanins and
phenolic acid; these compounds may account for up to
40% of the dry leaf weight. The major polyphenolic
fraction is the group of flavanols in green tea. The
(+)-Catechin (C) (+)-Gallocatechin (GC) green tea flavanols are commonly known as green tea
catechins. Some major green tea catechins are (-)-epi-
gallocatechin-3-gallate (EGCG), (-)-epigallocatechin
(EGC), (-)-epicatechin-3-gallate (ECG), (-)-epicatechin
(EC), (+)-gallocatechin (GC) and catechin (C) (Fig. 1)
(Graham, 1992). In the manufacture of black tea, the
Galloyl (G) “fermentation” process causes green tea catechins to
oxidize and form oligomeric flavanols, including
R1 R2 theaflavins, thearubigin and other oligomers. Theafla-
(-)-Epicatechin (EC) H H vins are a mixture of theaflavin (TF-1), theaflavin-
(-)-Epigallocatechin (EGC) OH H 3-gallate (TF-2a), theaflavin-3’-gallate (TF-2b) and
(-)-Epicatechin gallate (ECG) H G
(-)-Epigallocatechin gallate (EGCG) OH G theaflavin-3,3’-digallate (TF-3) (Fig. 2). However,
thearubigins are the most abundant phenolic fraction in
Fig. 1. Structure of green tea polyphenols. black tea, vary greatly in molecular weight, and have
structures are not yet well characterized. Partially fer-
mented oolong or paochong tea contains both green
genesis (Hertog et al., 1993a, 1993b). Consumption of tea catechins, black tea theaflavins and, possibly
tea on a regular basis has been associated with thearubigins. Some components in oolong or paochong
reduced risk of several forms of cancer in human pop- tea, such as proanthocyanidins, are less well character-
ulations and mouse models. There is strong evidence ized and they may be important in disease prevention.
linking green tea use to reduction in cancer risk in
parts of Asia (Dreosti et al., 1997). Multiple biological II. Inhibitory Effects of Tea Polyphe-
effects of flavonoids have been described, among then nols on Carcinogenesis in Exper-
anti-inflammatory, anti-allergic, anti-hemorrhagic, anti- imental Animals
mutagenic, anti-neoplastic and hepatopreventive activi-
ties. The flavonoids in green tea have been studied 1. Suppression of Carcinogenesis in Experime-
intensely in many laboratories. The major fraction of ntal Tumors
these flavonoids is the group of catechins in green tea.
Previous reports have reported that green tea catechins In 1983, Conney et al. were first to demonstrate
exhibited many biological functions, including anti-car- that hydroxylated flavonoids in tea had a potent
cinogenic activity. However, the molecular mechanisms inhibitory effect on mutagenic activity (Huang et al.,
of those flavonoids action were unclear. Thus, further 1983). Sugimura and his colleagues were first to use a
research has focused on gaining an understanding of two-stage skin carcinogenesis mouse model to demon-
the molecular mechanisms of flavonoids involved dis- strate that topical application of EGCG inhibited tumor
ease prevention. This report describes the anti-carcino- promotion induced by teleocidin in 7,12-dimethyl-
genic effects of tea flavonoids and the molecular benz(a)anthracene (DMBA)-initiated mouse skin
mechanisms which may be involved. (Yoshizawa et al., 1987). Studies by Mukhtar et al.
Tea (Camellia sinensis) has been used as a daily further showed that green tea polyphenols had a potent
beverage and crude medicine in China for several inhibitory effect on skin tumorigenicity in Sencar mice
thousand years. Tea beverages are primarily manufac- (Khan et al., 1988). In recent years, many studies
tured as green, black or oolong tea according to the demonstrated that topical application or oral feeding of
degree of fermentation invloved. Most Japanese and a polyphenolic fraction from tea extract, and individual
Chinese people in northern China prefer green tea catechin derivatives, had anticarcinogenic effects in
whereas Americans and Europeans prefer black tea. animal skin experiments (reviewed in Yang and Wang
Oolong and paochong teas are flavored in Taiwan and (1993) and Katiyar and Mukhtar (1997b)). Topical
parts of China. The composition of tea varies with the application or oral feeding of a green tea polyphenol
species, season, age of the leaf (plucking position), cli- fraction or its major component, EGCG, inhibited
mate, and horticultural practices (Lin et al., 1996, tumor initiation induced by DMBA and benzo(a)pyrene
–2–
Cancer Prevention by Tea Polyphenols
forms of EGCG might be effective against carcinogen-
esis. Katiyar et al. (1993c, 1993d) and Wang et al.
(1992a) reported that oral consumption of green tea
polyphenols or water extract of green tea afforded sig-
nificant protection against both N-nitrosodiethylamine
(NDEA) and benzo(a) pyrene (B[a]P)-induced fore-
stomach and lung tumorigenesis in A/J mice. Similar
(-)-Epigallocatechin-3-gallate Thearubigin, R=Galloyl
(possible structure)
results were also observed from green, or black tea
extract, EGCG, or theaflavins which were effective
against lung tumorigenesis induced by the tobacco car-
cinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) (Wang et al., 1992b; Xu et al., 1992; Shi et
al., 1994; Yang et al., 1997a, 1997b, 1998a). Witschi
et al. (1998) demonstrated a protective effect of green
tea extracts against tobacco smoke-induced lung tumors
in A/J mice. The progression of adenoma to adenocar-
Theaflavins Galloyl (G)
cinoma and the cell proliferation rate in adenomas
were also suppressed by black tea treatment. A recent
Theaflavins R1 R2
study showed that oral feeding of black tea extract
Theaflavin (Theaflavin-1; TF-1) H H
offered protection against lung tumorigenesis induced
Theaflavin-3-gallate (Theaflavin-2a; TF-2a) G H
Theaflavin-3’-gallate (Theaflavin-2b; TF-2b) H G by NNK in a 2-year life time bioassay in F344 rats,
Theaflavin-3,3’-digallate (Theaflavin-3; TF-3) G G and that caffeine may have been an important con-
stituent involved in inhibition of lung carcinogenesis
Fig. 2. Structure of black tea polyphenols. (Chung et al., 1998). When tea infusion was given to
rats in drinking water during an N-nitroso-methylben-
zylamine (NMBA) administration period, esophageal
diolepoxide (BPDE), as well as promotion induced by tumorigenesis was inhibited (Chen, 1992; Han and Xu,
TPA, teleocidin, and okadaic acid in Sencar or CD-1 1990). Recently, Morse et al. (1997) reported that only
mice skin (Fujiki et al., 1990; Wang et al., 1991, theaflavin significantly reduced esophageal tumor for-
1992d, 1994; Katiyar et al., 1992a, 1992b, 1993a, mation induced by NMBA in rats. Oral feeding of
1993b; Gensler et al., 1996). Topical application or EGCG (0.005%) in drinking water resulted in a reduc-
oral feeding of green tea polyphenols inhibited tumor tion of N-ethyl-N’-nitro-N-nitrosoguanidine (ENNG)-
formation when 3-methylcholanthrene (3-MC) or UV induced duodenum tumorigenicity in C57BL/6 mice
light was used as the carcinogenic agent (Wang et al., (Fujita et al., 1989). In a multiorgan carcinogenesis
1991, 1994; Gensler et al., 1996). However, Higashi- model in which F344 rats were pretreated with admin-
Okai et al. (1998) demonstrated that the non-polyphe- istration of several combined carcinogens, Hirose et al.
nolic fraction of green tea also inhibited tumor promo- (1993) found that 1% green tea polyphenols given dur-
tion in mouse skin. Huang et al. (1997) demonstrated ing or after the carcinogen exposure period inhibited
that caffeine also contributed in an important way to adenoma and adenocarcinoma formation in the small
the inhibitory effects of green tea and black tea on intestine. Chen et al. (1987) and Qin et al. (1997)
UVB-induced complete carcinogenesis. reported that 5% green tea leaf in the diet resulted in
In addition to preventive effects against skin car- significant inhibition of aflatoxin B1-induced hepato-
cinogenesis, many studies have shown that tea carcinogenesis in rats. When 2.5% green tea leaf was
polyphenols are effective against carcinogenesis given to rats in their diet, NDEA- induced hepatocar-
induced in internal organs. Several reports also found cinogenesis was also inhibited (Li, 1991). Studies by
that following oral administration of EGCG in rats or Matsumoto et al. (1996) demonstrated that tea cate-
humans, the absorption of EGCG was detected in the chins, black tea extract, and oolong tea extracts had
circulation system (Unno and Takeo, 1995; Unno et an inhibitory effect on the development of hepatocar-
al., 1996; Okushio et al., 1996). The highest concen- cinogenesis in rats. Hirose et al. (1994) and Tanaka et
tration of EGCG in rat or human plasma was detected al. (1997) reported on an inhibitory effect of green tea
60-120 min after administration and decreased quickly catechins on mammary gland carcinogenesis in female
thereafter. Tomita et al. (1997) reported that EGCG Sprague-Dawley rats pretreated with DMBA. Recently,
was also present in conjugated forms in plasma, Rogers et al. (1998) found that oral feeding of black
including glucuronide, sulfate and dimeric forms. All tea infusion and a high fat diet increased the inhibition
–3–
J.K. Lin and Y.C. Liang
of the promotion of DMBA-induced mammary tumori- also by Wang et al. (1992d), showed that green tea
genesis. Harada et al. (1991) and Majima et al. (1998) polyphenols and EGCG inhibited the growth of estab-
provided information about the chemopreventive effect lished skin tumors induced chemically or by UV light.
of green tea polyphenols against N-nitrosobis-(2-oxo- Oral, subcutaneous, or intraperitoneal administration of
propyl) amine (BOP)-induced pancreatic carcinogene- EGCG or green tea polyphenols in mice also resulted
sis in Syrian golden hamsters. A study by Hiura et al. in significant suppression of the growth of implanted
(1997) showed that green tea extract also had an tumor cells (Oguni et al., 1988; Hara et al., 1989;
inhibitory effect on tumor promotion after transplanta- Yan, 1992). Lu et al. (1997) reported that oral admin-
tion of N-nitrosobis-(2-hydroxy propyl) amine (BHP)- istration of black tea in tumor-bearing mice inhibited
induced pancreatic cancer in Syrian hamsters. proliferation and enhanced apoptosis in nonmalignant
In a rat colon carcinogenesis model, Yamane et and malignant skin tumors. Katiyar et al. (1997) found
al. (1991) demonstrated the inhibition of azoxymethane that green tea polyphenols protected against the induc-
(AOM)-induced colon carcinogenesis following oral tion and subsequent progression of papilloma to squa-
feeding of green tea polyphenols (0.01 or 0.1%, w/v) mous cell carcinomas in experimental animals. Landau
in drinking water in Fisher rats. However, little data et al. (1998) demonstrated that black and green tea
is available on the effect of tea extracts in reducing infusion significantly decreased the spontaneous forma-
the risk of colon cancer induced by AOM. Thus, com- tion of lung tumors and rhabdomyosarcomas in A/J
bination treatment using tea extracts and other sub- mice.
stances on AOM-induced colon cancer was studied by
Challa et al. (1997) and Weisburger et al. (1997). 3. Inhibitory Effects on Malignant Tumor In-
Challa et al. (1997) found that green tea had a mar- vasion and Metastasis
ginal effect (p < 0.14) on the incidence of aberrant
colon crypt foci. However, the interaction between Taniguchi et al. (1992) and Sazuka et al. (1995)
green tea and phytic acid was significant and positive, showed that preoral administration of green tea infu-
pointing to a synergistic effect of green tea and phytic sion or EGCG inhibited lung metastasis in mouse
acid. Weisburger et al. (1997) showed that oral feeding melanoma and Lewis lung carcinoma cells. This anti-
of 1.25% tea infusion and milk during the period of invasive activity may be due to binding with laminin,
carcinogen administration significantly decreased the leading to decreased adhesion of MO4 cells to the
production of aberrant colon crypts. The tea products extracellular matrix (Bracke et al., 1987, 1991).
did not, however, affect the development of colon can- Unpublished results from our laboratory also indicated
cer induced by AOM. The mechanisms underlying that EGCG suppressed lung metastasis produced by
those findings are related to the fact that AOM is B16-F3m melanoma cells in mice. The mechanisms of
metabolized mainly by cytochrome P450 2E1, and the antimetastatic effect of EGCG was associated to its
fact that this enzyme system is not affected by tea inhibition of cell spreading of tumor cells, suppression
products (Weisburger et al., 1998). Studies by Hartman of metallopritenase-9 (MMP-9) secretion, and serum-
et al. (1998) also supported the hypothesis that coffee induced tyrosine phosphorylation of focal adhesion
and tea are unable to protect against colorectal cancer. kinase (FAK). Sazuka et al. (1997) also reported that
Narisawa and Fukaura (1993) found that even a very the theaflavin digallate and EGCG inhibited MMPs
low dose of green tea polyphenols in drinking water secretion from culture medium of LL2-Lu3 tumor
could prevent N-methyl-N-nitroso urea (MNU)-induced cells.
colon carcinogenesis in F344 rats. Xu et al. (1996)
indicated that extracts of green tea and black tea III. Effects of Tea on the Incidence
offered protection against 2-amino-3-methylimidazo[4,5- of Human Cancer
f] quinoline-induced colonic aberrant crypts in F344
rats. The effects of tea consumption on the occurrence
of human cancers have been reviewed by the
2. Inhibitory Effects on Tumor Growth in International Agency for Research on Cancer Working
Mice with Established Papillomas Group based on the literature available in 1989 (IARC,
1991) and by Yang and Wang based on the literature
Tea and its polyphenolic components have been up to 1992 (Yang and Wang, 1993). A general con-
shown by many laboratories to inhibit various kinds of clusion regarding the relationship between tea con-
carcinogenesis as explained above. Some of these stud- sumption and cancer risk based on these studies, is,
ies showed that tea components also markedly reduced however, difficult to drow.
tumor size (Wang et al., 1990, 1992b). Another study, Among 100 epidemiology studies, including case-
–4–
Cancer Prevention by Tea Polyphenols
control, cohort and ecological studies, on the relation- 1. Inhibition of Mutagenicity
ship between tea drinking and human cancer, 28 stud-
Green, black and decaffeinated black tea were
ies showed a positive association, 58 studies showed
found to significantly inhibit the mutagenicity induced
no relationship and 14 studies showed a negative asso-
ciation between tea drinking and cancer incidence by three indirect-acting dietary carcinogens, Glu-p-1,
(Yang and Wang, 1993). Most of the studies that B[a]P and nitrosopyrrolidine, in a bacterial test system
showed no association or a positive one were carried (Bu-Abbas et al., 1996). Tea polyphenols sharply
out in Western countries while a negative association decreased the mutagenicity of a number of aryl-and
was mostly found in case-control studies in Asian heterocyclic amines, of aflatoxin B1, B[a]P, 1, 2-dibro-
countries, especially China and Japan, where inhabi- moethane, and more selectively, of 2-nitropropane in
tants daily drink large amounts of green tea or oolong Salmonella typhimurium (Weisburger et al., 1996). Yen
tea. The reason for this discrepancy has in part been and Chen (1996) studied the relationship between the
ascribed to the fact that heavy tea drinkers and tea chemical content and antimutagenic activity of various
lovers have been far fewer in study populations in tea extracts. The amount of catechins in various tea
Western countries than those in Asian countries. The extracts was in the order: green tea > oolong tea > pou-
different dietary conditions and habits between Western chong tea > black tea. The tea extracts of oolong and
and Asian populations may have been responsible for pouchong teas markedly inhibited the mutagenicity of
the different results obtained for the association of tea various carcinogens. Recently, we also examined the
drinking with cancer. antimutagenic properties of various tea extracts (green,
A recent prospective cohort study on a Japanese pauchong, oolong, and black teas) against different
population confirmed the effect of green tea in pre- groups of environmental mutagens. The results sug-
venting cancer (Imai et al., 1997). These authors used
gested that different degrees of tea fermentation might
four different approaches: a comparison of age-specific
produce different types of antimutagenic compounds
cancer incidence rates, a comparison of ages at cancer
effective against their corresponding mutagens (Hour
onset among cancer patients with different levels of
consumption of green tea, a comparison of age-stan- et al., 1999). Fumes from cooking oils were found to
dardized cancer incidence rates and examination of the have mutagenic activity. The results obtained by Wu
relative risk adjusted for other lifestyle population. et al. (1998) indicated that fumes from cooking oils
They thus found a negative association between green contained nitro- and polycyclic aromatic hydrocarbons
tea consumption and cancer incidence, especially (PAHs) which may be a risk factor for lung cancer
among females drinking more than 10 cups a day. A among cooks and showed that the amounts of carcino-
slowdown in the increase of cancer incidence with age gens could be reduced by adding catechin. Black tea
was observed among females who consumed more polyphenols were more potent inhibitors of mutagenic-
than 10 cups a day; consumption of green tea was ity than green tea ones caused by the food mutag-
associated with late onset of cancer. The age-standard- en 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine
ized average annual incidence rate was significantly (PhIP) in the Salmonella test system (Apostolides et
lower among females who consumed large amounts of al., 1996). Chen and Yen (1997) showed that tea
green tea. The relative risk of cancer incidence was extracts inhibited 2-amino-3-methylimidazo[4,5-f] quin-
also lower among both females and males in the high- oline (IQ) and B[a]P-induced mutagenicity in a Salmo-
est tea consumption groups. This prospective cohort nella/microsome assay. Their study revealed that tea
study showed that green tea had a potentially preven- extracts could inhibit the cytochrome P450-mediated
tive effect against cancer in humans (Imai et al., 1997;
metabolism of IQ and B[a]P into their ultimate muta-
Nakachi et al., 1998).
genic metabolite form, and interact with both promuta-
gens and their metabolites in such a way as to reduce
IV. Molecular Mechanisms of Can- their mutagenic potentials. Another study by Hernaez
cer Chemoprevention by Tea et al. (1998) also suggested that catechin might pro-
Polyphenols tect against such diverse reactive intermediates as free
The inhibitory effects of tea against carcinogene- radicals and electrophiles forms during the metabolic
sis have been attributed to the biologic activities of activation of IQ.
the polyphenol fractions in tea. However, the molecu-
2. Antioxidative Effects
lar mechanisms of cancer chemoprevention induced by
tea extracts are not fully understood. Some recent stu- Tea polyphenols are strong scavengers against
dies in our laboratory and others are discussed herein. superoxide, hydrogen peroxide, hydroxy radicals, and
–5–
J.K. Lin and Y.C. Liang
nitric oxide produced by various chemicals. Chen and plasma antioxidant potential in man. Their results
Ho (1994) extensively investigated the antioxidant showed that ingestion of tea produced a significant
properties of various tea polyphenols. Their study increase of human plasma antioxidant capacity. Lotito
showed that the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Fraga (1998) showed that (+)catechin prevented
radical-scavenging ability of various tea polyphenols human plasma from undergoing oxidation induced by
was EGCG > ECG > EGC > EC = TF-2 > TF-1 > TF. [2,2’-azobis-(2-amidinopropane) clorhidrate] (AAPH) or
The DPPH radical-scavenging activity was proportional [2,2’-azobis-(2,4-valeronitrile)] (AMVN).
to the number of -OH groups in the catechins or In addition, several reports indicated that tea
theaflavins. The superoxide-scavenging activity of the intake may enhance the levels of antioxidant defense
catechins was EGCG > ECG > EGC > EC. All the enzymes, such as SOD and catalase. An in vivo study
theaflavins exhibited the same ability to inhibit the was done by Khan et al. (1992) in which SKH-1 hair-
production of superoxide. The lipid oxidation-inhibition less mice were treated for 30 days with polyphenols
activity of the catechins was also EGCG > ECG > (0.2%, w/v) isolated from green tea in drinking water.
EGC > EC, which was the same trend found for the The results indicated that increased activities of cata-
DPPH radical-scavenging activity and the superoxide- lase and glutathione peroxidase were observed in the
scavenging activity. However theaflavins showed less hepatic, pulmonary, and small bowel. Bu-Abbas et al.
lipid oxidation-inhibition activity than catechins. (1995) found that treatment of rats with green tea
Previous studies in our laboratory examined the antiox- aqueous extracts as the sole drinking fluid for 4
idant activity of tea polyphenols by means of ORAC weeks, at concentrations consumed by humans, could
(oxygen-radical absorbance capacity) assay (Lin et al., increase the UDP-glucuronosyl transferase activity.
1996). The scavenging effects on the peroxyl radical Previous studies in our laboratory also found that after
were in the following order: EGCG > EGC > ECG > intraperitoneal injections of green tea polyphenols in
gallic acid > EC > C > caffeine. Leanderson et al. rats, the antioxidant and phase II enzyme activities
(1997) showed that green tea polyphenols inhibited were elevated (Lee et al., 1995). The structure of tea
both cigarette smoke- and H2O2-induced DNA break- polyphenols might consist of strong metal ion chela-
age in cultured lung cells. Green tea, black tea and tors, such as iron and copper, which are required for
EGCG were shown to block the production of oxygen generation of reactive oxygen radicals by means of
free radicals derived from IQ in the presence of Fenton and Haber-Weiss reactions. Miller et al. (1996)
NADPH-cytochrome P450 reductase (Hasaniya et al., showed that the antioxidant properties of theaflavins
1997). Peroxynitrite is a cytotoxic species generated by and their gallate ester might through chelating iron and
the reaction between superoxide and nitric oxide. copper. Recently, we found that oral feeding of green
Catechin polyphenols could also decrease the perox- tea leaves to rats resulted in enhanced SOD activity in
ynitrite-induced nitration of tyrosine and protect serum and catalase activity in liver, and an increased
apolipoprotein B-100 of LDL from peroxynitrite- concentration of glutathione in the liver (Lin et al.,
induced modification of critical amino acids, which 1998b).
contribute to its surface charge (Pannala et al., 1997).
Kaneko et al. (1998) found that catechin was effective 3. Modulation of Metabolizing/Detoxifying En-
in suppressing linolic acid hydroperoxide (LOOH)- zymes
induced cytotoxicity, but that EC, EGC, ECG, and
EGCG had no effect. Most procarcinogens require metabolic activation
Recently, several studies have found that black by metabolite enzymes, such as phase I and II
tea and green tea offered protection against oxidative enzymes, in order to convert to electrophiles before
damage to red blood cells induced by a variety of they can exert carcinogenic effects (Conney, 1982).
inducers, e.g., H 2O 2, primaquine, 2,2’-azo-bis(2- Tea polyphenols have been shown to effectively inhib-
amidinopropane) dihydrochloride (AAPH), phenylhy- it tumorigenesis induced by various carcinogens in the
drazine (PHx), Cu2+-ascorbic acid, and the xanthine/ skin, lung, forestomach and esophagus of rodents as
xanthine oxidase system (Grinberg et al., 1997; Zhang described above. Green tea polyphenols have been
et al., 1997; Halder and Bhaduri, 1998). Oral adminis- found to inhibit rat liver microsomal mono-oxygenase
tration of green or black tea leaf powder inhibited the activities, including phase I enzymes of aryl hydrocar-
lipid peroxidation of liver induced by tert-butyl bon hydroxylase, 7-ethoxyresorufin O-deethylase, and
hydroperoxide in rats (Sano et al., 1995) while in the 7-ethoxycoumarin O-deethylase (Wang et al., 1988).
kidney, the antioxidant effect was observed only for Another report indicated that treatment of rats with
the green tea-fed group. Serafini et al. (1996) demon- green and black tea for 4 or 6 weeks caused signifi-
strated the antioxidant effect of green and black tea on cant induction of cytochrome P450 enzymes, such as
–6–
Cancer Prevention by Tea Polyphenols
CYP1A2, CYP1A1, CYP2B, and CYP4A1 (Sohn et 1997; Chen et al., 1999). The cyclooxygenase and
al., 1994; Bu-Abbas et al., 1994). Induced phase I lipooxygenase pathways of arachidonic acid metabo-
enzymes might be metabolic activators of carcinogens, lism may be involved in carcinogenesis, especially in
for example, CYP1A2 may play an important role in the promotion of cell proliferation, e.g., colon cancer.
the activation of aromatic and heterocyclic amine pro- Inhibitory effects of green tea polyphenols on TPA-
carcinogens. However, Chen et al. (1996) reported that induced mouse epidermal lipooxygenase and cyclooxy-
decaffeine green tea polyphenols did not caused sig- genase activities in vivo have been observed (Katiyar
nificant induction of CYP enzymes. It is possible that et al., 1992b). Dong et al. (1997) showed that EGCG
the induction of CYP1A2 was an effect of caffeine. and theaflavins inhibited epidermal growth factor- or
Chronic oral administration in mice of 0.2% green tea TPA-induced cell transformation in a dose-dependent
polyphenols in drinking water for 4 weeks significantly manner. The molecular mechanism of the antipromo-
enhanced the activities of phase II detoxifying en- tion activity of EGCG and theaflavins involves block-
zymes, such as glutathione-S-transferase (GST), glu- ing of the AP-1-dependent transcriptional activity and
tathione peroxidase, catalase, and NADPH-quinone oxi- DNA binding activity. The inhibition of AP-1 activa-
doreductase, in the small bowel, lung and liver (Khan tion occurs through the inhibition of a c-Jun NH2-ter-
et al., 1992). Bu-Abbas et al. (1995) showed that minal kinase-dependent, but not an extracellular signal-
treatment with green tea resulted in stimulation of rat regulated protein kinase (ErK) 1-dependent or Erk2-
hepatic UDP-glucuronosyl transferase activity. It is dependent pathway. Recently, we proposed that the
known that 5' flanking regions of phase II genes con- molecular mechanisms of antitumor promotion might
tain several cis-acting regulatory elements, such as the operate by blocking the mitotic signal transduction
antioxidant-responsive element (ARE)/electrophile- pathway (Lin and Lee, 1995; Lin et al., 1997, 1999a).
responsive element and xenobiotic-responsive element We demonstrated that the major and most potent com-
(XRE)/ aromatic hydrocarbon-xenobiotic responsive ponent of tea polyphenol EGCG and TF-3 strongly
element, which are thought to mediate the induction inhibited the kinase activity of EGF and PDGF recep-
by many drugs of phase II enzyme (Friling et al., tors induced by EGF or PDGF, respectively (Liang et
1990; Prestera and Talalay, 1995). Yu et al. (1997) al., 1997, 1999a). Additional studies showed that both
demonstrated that green tea polyphenols may induce EGCG and TF-3 blocked EGF from binding to its
phase II detoxifying enzymes through the ARE but not receptor. These results suggested that EGCG and TF-3
through the XRE as a result of transcriptional activa- have an antiproliferation effect on tumor cells, and that
tion of the ARE-dependent or XRE-dependent CAT the molecular mechanisms of this effect may block the
reporter gene in the Hep G2 cell line. Unpublished growth factor binding to its receptor, and subsequently
data from our laboratory indicated that EGCG in- through inhibition of receptor kinase activity, and sup-
creased the expression of a phase II conjugation press mitogenic signal transduction.
enzyme, GST, in a rat normal cell line, NRK-49F. Tea polyphenols might suppress mitogenic signal
Additional studies indicated that EGCG could enhance transduction and other unknown proliferative signals.
the binding activity of ARE but not of XRE. These effects might have an inhibitory effect on pro-
liferation and cell cycle progression, even on apopto-
4. Inhibition of Activities Related to Tumor sis. Lea et al. (1993) reported that EGCG or green
Promotion, Proliferation and Mitotic Signal and black tea polyphenols strongly inhibited DNA syn-
Transduction thesis in DS19 mouse erythroleukemia cells and HTC
rat hepatoma cells. Valcic et al. (1996) demonstrated
The induction of ODC, PKC, protein kinase that green tea polyphenols inhibited the growth of four
activities, and oxidative stress by TPA is believed to selected human tumor cell lines, including MCF-7
be closely related to the tumor promotion activity of breast carcinoma, HT-29 colon carcinoma, A-427 lung
this compound (Lin and Lee, 1995). Topical applica- carcinoma and UACC-375 melanoma. Chen et al.
tion of green tea polyphenols to mouse skin was found (1998) compared the effect of EGCG on the growth
to inhibit TPA-caused induction of ODC activity in a of SV-40 virally transformed WI38 human fibroblasts
dose-dependent manner (Agarwal et al., 1992). (WI38VA) with that of normal WI38 cells. The results
Similarly, the topical application of EGCG resulted in indicated that EGCG had a pronounced growth
significant inhibition of TPA-caused induction of epi- inhibitory effect on cancerous cells (WI38VA) but not
dermal ODC activity (Katiyar et al., 1992a). Our stud- on their normal counterparts. Similar differences in
ies demonstrated that EGCG and TF-3 inhibited TPA- growth inhibition were also observed between a human
induced transformation, PKC activation and AP-1 bind- colorectal cancer cell line (Caco-2), a breast cancer
ing activities in mouse fibroblast cells (Lee and Lin, cell line (Hs578T) and their respective normal coun-
–7–
J.K. Lin and Y.C. Liang
terparts. The proliferation of vascular smooth muscle sion of iNOS mRNA, and that the reduction could
cells was strongly inhibited only by EGC, and this occur as a result of prevention of binding of the
inhibition involved the inhibition of JNK activity (Lu nuclear factor- κB to the iNOS promoter, thereby
et al., 1998). inhibiting the induction of iNOS transcription (Lin and
Some reports indicated that EGCG could induce Lin, 1997)
apoptosis in human prostate and stomach cancer cell
lines, and in other cell lines (Ahmad et al., 1997; V. Conclusion
Paschka et al., 1998; Hibasami et al., 1998). More-
over, Yang et al. (1998a, 1998b) showed that tea Although the anticarcinogenic activities of tea
polyphenols displayed strong growth inhibitory effects polyphenols have been demonstrated in many animal
against a lung tumor cell line. When cultured cells studies, epidemiologic evidence for a protective role of
with EGCG produced H2O2 in a dose-dependent man- tea consumption against cancer in human populations
ner. The results suggested that tea polyphenols-induced is weak (Kohlmeier et al., 1997). These inconsisten-
production of H2O2 may mediate apoptosis, and that cies might majority intake insufficient tea polyphenols
this may contribute to the growth inhibitory activities for against human cancer incidence. Some preclinical
of tea polyphenols in vitro. Several reports showed studies have demonstrated that consuming four cups
that tea polyphenols could modulate the cell cycle pro- (800 ml) of green tea daily results in ingestion of 17.7
gression of tumor cells. Ahmad et al. (1997) showed µmol EGCG/kg-bw/day, which is comparable to the
that A431 cell treatment with EGCG resulted in the lowest (0.016 mmol/kg-bw/day) effective dose in ani-
arrest of the G0-G1 phase of the cell cycle. Fujiki et mal models (Yang et al., 1995; Unno and Takeo,
al. (1998) reported that tea polyphenols inhibited the 1995). However, the effects of tea polyphenols on the
growth of a human lung cancer cells line, PC-9 cells lung and skin in several preclinical studies suggested
with G2/M arrest. Primary cultured of oral epithelial that these are the most likely target organs for future
cells were treated with EGCG, and the cell cycle pro- clinical chemoprevent trials. Additionally, based on the
gression arrested in G1 phase (Khafif et al., 1998). results of numerous laboratory studies, we believe that
Recently, we found that EGCG exerted growth tea consumption is likely to have beneficial effects in
inhibitory effects on human breast cancer cells through reducing some cancer risk of humans. A great deal of
either modulation of the activities of several key G1 data has demonstrated that tea consumption might
regulatory proteins, such as cyclin-dependent kinase reduce the risk of certain cancers. A clear understand-
(Cdk) 2 and 4, or through mediation of the induction ing of the chemical properties of tea and the mecha-
of Cdk inhibitors p21 and p27 (Liang et al., 1999b). nisms by which tea components may affect the car-
cinogenesis of specific cancers are important issues
5. Antiinflammatory Effects and deserve for further exploring.
The induction of inflammation in skin mediated Acknowledgment
by TPA is believed to be governed by cyclooxygenase
(COX), lipooxygenase and ODC. These markers of This study was supported by the National Science Council
of the Republic of China under grants NSC 88-2316-B-002-015,
inflammatory responses are important for skin tumor
NSC 88-2621-B-002-004-Z and NSC-EPA-Z-002-021 and by the
promotion. Katiyar and Mukhtar (1997a) demonstrated National Health Research Institute of the Republic of China under
that pre-application of black tea polyphenols to that of grant DOH-88-403.
TPA resulted in significant inhibition of TPA-caused
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