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Introduction
Prostate cancer (PCa), one of the most invasive and most
frequently diagnosed male malignancies in the United States,
is the second leading cause of cancer-related deaths in
American males with similar trends in other western
countries[1]. In the year 2002, 679 023 new cases were reported worldwide
and the disease killed 221 002 (three-quarters of all cases are
in men aged 65 or more) making this the fifth most common
cancer in the world and the second most common in men
(11.7% of new cancer cases overall; 19% in developed
countries and 5.3% in developing
countries)[2]. According to a projection by the American Cancer Society, approximately
218 890 men will be diagnosed with PCa in the USA in the
year 2007, and 27 050 PCa-related deaths are
predicted[1]. The incidence of PCa increases rapidly with advancing age,
and multiple genetic and epigenetic factors have been
implicated in the development of PCa. Despite the substantial
morbidity and mortality, the etiology of PCa is poorly
understood. The limitations in the clinical management of
PCa are derived not only from the fact that no single gene or
molecule has served as a reliable marker of PCa but also from
the reality that, as yet, an effective therapeutic regimen for
its treatment is lacking. It is increasingly appreciated that
environment and lifestyle, particularly dietary habits, also
contribute substantially to the disease
outcome[3]. It is of interest that in western countries PCa is more prevalent than
their eastern counterparts, possibly due to the varied
divergence in their dietary habits (Figure 1).
Evidence from geographic, epidemiological
and in-vitro and in-vivo experiments suggest that environmental
carcinogenic factors and nutrition play important causative roles
in the initiation, promotion and progression of
PCa[4_7].
Although clinical PCa incidence and mortality vary greatly
among populations[3,8], the frequency of latent PCa is evenly
distributed. The rising incidence of PCa in several countries
that previously were considered to have low incidence rates
appear to be coincident with the adoption of western lifestyle
in those populations, implicating factors such as low levels
of physical activity, high relative body weight and high
dietary fat intake in the pathophysiology of
PCa[9]. While environmental carcinogenic factors are difficult to control,
dietary habits can easily be modified based only on
individual decisions.
One case-control study has shown a positive
association of PCa risk with total energy intake, as well as total fat
intake[10]. These observations, combined with an improved
understanding of the molecular biology of the disease
provide leads to explore testable PCa prevention strategies.
Current treatment strategies such as hormone therapy,
radiation and surgery are proving useful in reducing the
mortality associated with PCa, however, malignant and
non-malignant tumors continue to progress and become refractory
to these treatment options. Although, these treatments
provide a limited success in reducing the mortality in PCa
patients, the severe side effects of these treatments have
also been reported. These include rectal complications,
urinary incontinence, and impotence, loss of libido, weight gain,
gynaecomastia, liver inflammation, and
osteoporosis[11]. Because PCa is a complex process that involves different
molecular events, usually occurring simultaneously,
blocking or inhibiting only one event will not be sufficient to
prevent or delay the onset of the disease. It is therefore
necessary to intensify our efforts for a better understanding of
PCa pathophysiology, and for the development of novel
approaches for its prevention and treatment. Among many
preventive approaches chemoprevention through the use
of non toxic dietary substances is gaining
popularity[12,13].
Many types of natural agents that act on various
molecular targets have been reported to inhibit or delay various
stage(s) of cancer[12,13]. Epidemiological studies have shown
a correlation between populations with higher consumption
of selenium and vitamin E, fruits and tomatoes, in lowering
the risk of PCa[14,15]. Consistent with this notion, several
single natural agents are currently being studied for their
potential as preventive agents against PCa. Tea derived
from the plant Camellia sinensis, has been studied
extensively and shown to have anti-mutagenic and anti-cancer
effects in animal tumor models[16,17]. In 1999, we initiated a
program to assess whether tea consumption could afford
chemopreventive effects against prostate
carcinogenesis[18], which we continue to pursue. This research has also been
extensively followed in many laboratories around the world.
In this review we summarize the laboratory studies, clinical
trials and epidemiological observations supporting the use
of tea or its individual constituent polyphenols in
prevention and/or better management of PCa.
Chemoprevention and prostate cancer
The magnitude of the problem of cancer and the failure
of conventional strategies to effect a marked diminution in
the total number of deaths from this disease now indicate
that other preventive or therapeutic measures should be
seriously explored. Many strategies are possible to reduce
cancer-related deaths, four of which are noteworthy: (1)
prevention; (2) early diagnosis and intervention; (3)
successful treatment of localized cancer; and (4) improved
management of non-localized cancer. Among these, prevention
appears to be the most practical approach. One approach
for preventing the occurrence of cancer(s) is through
chemoprevention. Chemoprevention, by definition,
is a means of cancer control in which the occurrence of the
disease can be entirely prevented, slowed or reversed by
the administration of one or more naturally occurring
and/or synthetic
compounds[19_23]. This approach is promising
because therapy and surgery have not been fully effective
against the high incidence and/or low survival rate of most
cancer types. Furthermore, this approach with the use of
dietary substances appears to have practical implications in
reducing cancer risk because unlike the carcinogenic
environmental factors that are difficult to control, individuals
can make decisions to modify the food and beverages they
consume.
Chemoprevention, especially through consumption of
tea, appears to be a useful strategy for the management of
PCa. This is well-supported by the epidemiological
observation that the Japanese and Chinese populations, which
are habitual drinkers of several cups of tea, have one of the
lowest rates of PCa in the world[24]. PCa is believed to be an
ideal candidate disease for chemoprevention because of its
high latency period and because it is typically diagnosed in
men over the age of 50. Thus, even a slight delay in the
progression of this disease by chemoprevention could
result in substantial reduction in the incidence of the disease
and more importantly, improve the quality of life of the
patients with the disease[25,26]. If chemoprevention delays the
clinical course of PCa even by 5 years, the incidence of and
deaths from this disease would decrease
substantially[27]. The identification of promising agents (and their molecular
targets) for PCa prevention is guided by data derived from a
variety of sources. These evidence-based leads come from
(1) epidemiological observations; (2) PCa clinical trials; (3)
secondary analyses from large, randomized, controlled
cancer clinical trials; (4) understanding the mechanism of
prostate carcinogenesis; and (5) experimental animal models.
Tea: an overview
Tea, made from the leaves of Camellia
sinensis, an evergreen shrub of the
Theaceae family, is a beverage of choice in many countries around the world. The first instance of tea
drinking dates back to 2737 BC. According to a Chinese
legend, it was Emperor Shen Nung of China who accidently
discovered the refreshing effects and fine taste of tea when
he was out camping and a few leaves of a tea plant fell into
his cup of boiling water. Currently tea plant is cultivated in
approximately 30 countries. Based on the method of
processing, tea is typically of three types: black, green and
oolong. Black tea, predominantly consumed in Western and
some Asian countries, shares a major part of world tea
production, accounting for about 78% of total tea
consump-tion. About 20% of the total tea manufactured is green tea,
and is mainly consumed in China, Japan, India, and a few
countries in North Africa and the Middle East. The
remaining 2% of tea consumed is oolong tea, mainly produced and
consumed in southeastern China.
Tea contains several polyphenolic components, which
are antioxidative in nature, and many studies have shown
that tea polyphenols possess the ability to prevent
oxidant-induced cellular damage[28,29]. In recent years, studies from
ours and many laboratories around the world, conducted in
various organ-specific animal bioassay systems, have shown
that tea and its polyphenolic constituents are capable of
affording protection against a variety of cancer
types[13,16,19,29]. Although most of the studies conducted have used green
tea, a limited number of studies have also shown the
anti-cancer efficacy of black tea.
Tea as a beverage is consumed worldwide at greatly
varying levels. Not only does tea consumption vary from
country to country, but also there is enormous variation within a
given population. This ranges from no tea to as many as 20
or more cups per day. Although definite data are not
available, it is generally accepted that next to water, tea is the
most consumed beverage in the world; with a per capita
worldwide consumption of approximately 120 mL per
day[30].
The composition of tea-leaf varies with climate, season,
horticultural practices, variety of the plant, and the position
of the leaf on the harvested shoot (ie, its age). The
composition of different types of teas varies according to the
manufacturing process, which differs in the degree of `enzymatic
oxidation' or fermentation. Thus, green tea is unfermented,
oolong tea is partially fermented, and black tea is fully
fermented. Table 1 shows the principal polyphenolic
components present in a typical green and black tea beverage,
but variations may be considerable. Oolong tea
composition in general falls between that of green and black
teas[31].
Polyphenols of tea
Tea leaves are quite unique in that they are a rich source
of catechins, theanine and methylxanthines (Table 1). The
chemical composition of green tea is more or less similar to
that of the fresh leaf with regard to the major components.
Green tea contains polyphenolic compounds, which include
flavanols, flavandiols, flavonoids, and phenolic acids. These
compounds account for up to 30% of the dry weight of green
tea leaves. Most of the polyphenols present in green tea are
flavanols, commonly known as catechins. Some major
catechins present in green tea are (-)-epicatechin (EC),
(-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin (EGC), and
(-)-epigallocatechin-3-gallate (EGCG). The chemical
structures of these compounds are given in Figure 2. In addition,
caffeine, theobromine, theophylline, and phenolic acids such
as gallic acids are also present in green tea (Table 1). Green
teas are generally produced in two different varieties; white
tea and yellow tea, the latter is less fermented because of a
process known as wilting. In the production of black and
oolong tea, fresh leaves are allowed to wither until the
moisture content of the leaves is reduced to about 55% of the
original leaf-weight resulting in the concentration of
polyphenols and the deterioration of leaf-structural integrity. The
withered leaves are rolled and crushed, initiating
fermentation of the polyphenols. This process is known as maceration.
During these processes the catechins are converted to
theaflavins (TF) and thearubigins. TF are astringent
compounds contributing importantly to color and taste of black
tea. The thearubigen fraction is a mixture of substances,
with a molecular weight distribution of 1 000_40 000 and
account for 15% of dry weight solids of black tea. Oolong
teas are prepared by firing the leaves shortly after rolling to
terminate the oxidation and drying the leaves. Normal oolong
tea is considered to be about half fermented compared to
black tea. Oolong tea extracts contain catechins at a level of
8%_20% of the total dry matter.
During the fermentation process involved in the
manufacture of black tea, the monomeric flavanols undergo
polyphenol oxidase-dependent oxidative polymerization
leading to the formation of bisflavanols, TF, thearubigins, and
some other oligomers. TF (1%_2%, on dry weight basis)
contains benzotropolone rings with dihydroxy or trihydroxy
substitution systems. About 10%_20% of the dry weight of
black tea is due to thearubigens, which are even more
extensively oxidized and polymerized. The structures of TF and
thearubigins are shown in Figure 2. Oolong tea contains
monomeric catechins, TF, and thearubigins. In addition,
epigallocatechin esters, theasinensins, dimeric catechins, and
dimeric proanthocyanidins are also the characteristic
components of oolong tea.
Biochemical properties of tea and its poly-phenols
Tea is consumed worldwide for a variety of reasons from
improving blood flow, eliminating toxins and improving
resistance to various diseases and combating two of the
greatest killers of human population: cancer and cardiovascular
diseases. Supportive scientific evidence for these claims,
based on the data generated in recent times have lead to an
increase in consumption of green tea. The most widely
recognized biological properties of tea polyphenols are the
antioxidant properties[30,32]. Studies have shown that tea or
EGCG can lower lipid absorption and plasma lipid levels in
rats[33], increase high-density lipoprotein cholesterol in
humans[34] and decrease blood
glucose[35,36]. The health beneficial effects of tea and its polyphenols have been
summarized recently in a review from our
laboratory[30].
Several studies have suggested that the polyphenols,
present in tea possess high antioxidant activities, which in
turn, protects cells against the adverse effects of damaging
reactive oxygen species (ROS) such as superoxide radical,
hydroxyl radical, singlet oxygen, hydrogen peroxide,
peroxynitrite, and alkoxyradicals that are constantly produced
in the body. These ROS damage lipids, proteins, nucleic
acids, and cellular components such as ion channels,
membranes, and chromatin leading to cellular injury and
cellular dysfunctions and thus contribute to the etiology of
many chronic health problems including inflammatory
diseases, diabetes, obesity, cancer and cardiovascular
diseases[29,30,37,38]. Studies in culture systems have shown that
both green tea extract and ECGC are capable of inhibiting
the growth of a variety of mouse and human cancer cell
types[13,19,30]. Ahmad et
al[39] initially reported these effects
showing that green tea polyphenol (GTP) may protect against
cancer by causing cell cycle arrest and inducing apoptosis
in various carcinoma cells without affecting normal cells.
Some of the effects of tea polyphenols may also be due
to the chelation of metal ions. Because of its chelating
properties, tea may additionally protect against toxicity due
to heavy metals. Tea manifests chelating
activity in-vivo as indicated by the fact that tea consumption lowers
absorption of dietary iron in controlled feeding studies and
decre-ases body iron balance[40]. This study had also shown that
EGCG may chelate cations, which contribute to its ability to
inhibit angiotensin-converting enzyme. Tea polyphenols
chelate copper ions and this mechanism has also been
suggested to protect low-density lipoproteins from
peroxi-dation[41]. Catechins may also affect signal transduction
pathways, modulate many endocrine systems, and alter
hormones and other physiological processes as a result of their
binding these metals and enzyme
co-factors[42]. Tea polyphenols have been shown to inhibit the activation of
transcription factors AP-1 and NF-κB and synthesis of nitric
oxide[43_46]. Inhibition of cell transformation and cell growth by purified
catechins and TF has been reported [47]. These activities
have been attributed to the inhibition of AP-1 activity,
possibly due to the inhibition of several steps of signal
transduction pathways [eg, mitogen-activated protein kinase
(MAPK) activities by tea
polyphenols][48]. It has been reported that tea and its polyphenolic constituents impart
inhibitory effects on the activities of many enzymatic and
metabolic pathways relevant to cancer
development[49].
Tea and its constituents in the management of PCa
For many years the concept of management of PCa by
means of dietary intervention has been the subject of
increasing attention and discussion[50]. Epidemiological
studies show that in Asian populations that consume tea, the
incidence of all types of cancer including PCa is low
compared to that in the
West[3,8,24,51,52]. Thus, it has been
suggested that the low occurrence of PCa in Asian countries
may be due, in part, to the consumption of green tea by
these populations.
In the year 1999, our laboratory initiated a program to
assess the effect of tea consumption on prostate
carcino-genesis. Because the role of the androgen-responsive gene,
ornithine decarboxylase (ODC), the key regulatory enzyme
in the biosynthesis of polyamine is well documented in
carcinogenesis[53], we analyzed ODC activity in paired benign
and cancer tissues obtained from same individual with PCa
and found that ODC activity in cancer tissue was 2.7-fold
higher than in the corresponding paired benign tissue. This
exciting observation suggested that ODC could be
extrapolated as a target for prevention and therapy of PCa.
Extending these studies we investigated the effect of the
polyphenolic fraction isolated from green tea (GTP) against
testosterone-mediated induction of ODC in (1) LNCaP cells; (2)
Cpb:WU rats; and (3) C57BL/6 mice; and found that GTP resulted
in a significant reduction in testosterone-mediated
induction of ODC activity in the
prostate[18]. We then reasoned that these studies should be extrapolated and GTP should
be able to inhibit PCa development in an appropriate animal
model of PCa. Transgenic adenocarcinoma of the
mouse prostate (TRAMP) is one such model for PCa that closely
mimics progressive forms of the human
disease[54]. In this model, we provided convincing evidence that oral infusion
of GTPs (equivalent to 6 cups of green tea consumption in
humans) inhibits prostate
carcinogenesis[55,56]. The outcome of this study was later verified by Caporali and colleagues
who demonstrated that GTC significantly inhibited PCa
development in TRAMP mice[57]. This study further
demonstrated that in TRAMP mice, the clusterin gene was
dramatically downregulated during onset and progression of PCa.
In the GTC-treated TRAMP mice in which tumor
progression was chemoprevented, clusterin mRNA and protein
progressively accumulated in the prostate gland. The clusterin
levels returned to undetectable levels in animals in which
GTC chemoprevention failed and PCa developed.
Below, we summarize the biological activities of tea and
its constituents in relation to PCa.
Effect of tea polyphenols on androgen synthesis and
androgen receptor Because androgens are capable of both
stimulating proliferation as well as inhibiting the rate of
glandular epithelial cell death within the prostate, androgen
ablation therapy is commonly suggested for men with this
non-organ confined disease[58]. Huggins
et al for the first time demonstrated the use of androgen deprivation as a
treatment for advanced PCa[59]. Since then removal of
androgenic stimulation has been used to treat this disease.
Kao et al[42] reported that treatment with EGCG (85 mg/kg body
weight) for 7 d reduces the circulating testosterone levels by
70% in a murine model that can be associated with the
lowering of PCa risk. Studies that followed have shown that tea
polyphenols might block the pathway that leads to the
synthesis of androgen. Populations with impaired androgen
metabolism such as hereditary 5α-reductase deficiency do
not develop PCa, while those with higher circulating levels
of androgen are at a higher risk of the
disease[60]. In tumor xenograft studies of PCa, the
5α-reductase inhibitors
were found to slow the growth of previously established
tumors[61]. It has been reported that green tea constituents,
EGCG and ECG, inhibit the activity of type 1 rat
5α-reductase[62]. These polyphenols also inhibited types 1 and 2 human
5α-reductase in microsomes from rat cells that expressed the
human enzyme. Several molecular mechanisms have been
postulated to be accountable for the development of
sporadic hormone-refractory tumors. Most of these mechanisms
involve alterations in the function of the androgen receptor
(AR) and its complex signaling
pathways[63]. Several studies have demonstrated that AR is expressed in all of the
stages of PCa, and at least one-third of advanced PCa
contain amplified AR genes[64_66]. It is suggested that
overexpres-sion or mutation of the AR in PCa cells may promote a growth
advantage. Therefore, it has been of great interest to seek
more effective means of minimizing or eliminating the
function of the AR in order to achieve preventive and/or
therapeutic treatments for prostatic neoplastic disease. One study
reported that tea polyphenols downregulated the
expression of the AR in androgen responsive to LNCaP prostate
carcinoma cells[67]. They reported a significant reduction in
AR mRNA by the EGCG treatment. The basal activity of the
AR promoter is determined by an Sp1 binding site within the
AR core promoter region[68,69]. Sp1 not only regulates the
basal expression of the AR but also acts as its coregulator[70]. Sp1 is involved in the expression of genes related to
cell proliferation[71]. Since Sp1 regulates the expression of
many critical genes, the decrease in this protein by tea
polyphenols could somewhat decrease the growth rates of
prostatic cells. EGCG has been reported to significantly
decrease the Sp1 DNA binding
activity[67]. However additional
work is necessary to authenticate the effect of tea
constituents on androgen synthesis or its receptor status in a
manner that could lead to protection against development of
PCa.
Effect of tea polyphenols on prostate specific
antigen Prostate specific antigen (PSA) is a glycoprotein
secreted by the prostate gland. Functionally, PSA is a
kallikrein-like serine protease produced by the epithelial cell
lining of the acini and ducts of the prostate
gland[72]. It circulates in the serum in both free (unbound) and complex
forms. The most common cause for an elevated serum PSA
is benign prostatic hyperplasia, the incidence of which
increases with age, similar to PCa. Reduction in serum PSA
levels has been proposed as an endpoint biomarker for
staging hormone-insensitive human PCa intervention. At
present, the measurement of serum PSA levels is the most
commonly used biomarker for monitoring the progression of
PCa and the response to therapy[66]. It has been suggested
that serum PSA levels can be decreased by the agents that
lower serum testosterone levels such as leutinizing hormone
releasing hormone agonists and antagonists, anti-androgens
such as flutamide and bicalutamide, and the 5α-reductase
inhibitors such as finasteride[73,74]. We evaluated the effect
of EGCG on the production of PSA in androgen-sensitive
human prostate carcinoma LNCaP cells. This study
demonstrated that EGCG treatment resulted in significant dose-dependent decrease in PSA level in the culture medium.
Further, a significant time-dependent decrease in PSA
production was also observed after EGCG treatment compared
with the control. The validity of these cell culture
observations to human PCa patients could have implications in
reducing PCa body burden. Therefore, clinical data where
PSA levels are being monitored after administration of green
tea to PCa patients could be of interest.
Polyamine synthesis and tea polyphenols Polyamines
are present in all living cells and are essential for cell
differen-tiation, proliferation[75] and
migration[76]. Depletion of polyamines results in the inhibition of cell proliferation and
migration and the failure of embryonic development, whereas
accumulation of polyamines causes
apoptosis[77,78] or cell
transformation[79,80]. Cells maintain intracellular polyamines
at optimal levels by regulating synthesis or degradation and
by uptake or release of polyamines from or to the exterior.
Prostate tissue is known to contain some of the highest
concentrations of polyamines and polyamine-metabolizing
enzymes in the body[81,82]. ODC is a key regulatory enzyme
for polyamine synthesis and the induction of its activity has
been reported to be linked with various types of cancers
including PCa[53,83_85] and thus, ODC has been used as a
biomarker for the chemopreventive
studies[86]. An induction in the ODC activity and ODC mRNA expression mediated by
testosterone has been reported in prostate carcinoma
cells[87,88]. Our laboratory reported that GTPs significantly
reverse the induction of ODC activity as well ODC mRNA
expression in LNCaP cells[18]. We also demonstrated that
testosterone when administered to the C57 BL/6 mice, caused
a 2-fold increase in ODC activity in the ventral prostrate
while prior oral infusion of 0.2%
(w/v) GTP in drinking water resulted in 40% inhibition in this induction. In a recent study
EGCG was shown to decrease both tumor number and total
tumor burden compared with untreated ODC/Ras mice
without decreasing the elevated polyamine levels present in the
ODC/Ras mice[89].
Tea polyphenols and gene expression Cancer is believed
not to be a single disease but rather a conglomeration of
several diseases and several genes are known to play
imperative roles at various stages and at different levels in it.
These include the genes that regulate growth, cell signaling,
differentiation, cell death, cell division and cell migration.
There is always an upregulation or suppression of such
genes in the process of cancer development. Tea
polyphenols have been shown to modulate the function of various
genes at various levels. We identified nine genes, including
six kinases and three phosphatases, whose expression was
found to be downregulated by EGCG[90]. The genes repressed
by EGCG mostly belonged to the G-protein signaling
network and are responsible for cell proliferation, and include
adenosine kinase, protein kinase C alpha (PKC-α) and type I
β cGMP-dependent protein kinase. Interestingly, the
PKC-α form, whose inhibition of expression has been shown to
inhibit cell growth in some cancer cells, was selectively
repressed by EGCG while the expression of six other PKC
isoforms (β, δ, ε, μ, η and ζ) was
unaffected[90]. PKC is known to be involved in several diverse cellular functions including
cell differentiation, growth control, tumor promotion and
progression and cell death. It is also a regulator of cell cycle
events during G1 progression and G2/M transition.
Inhibition of PKC-α gene expression is believed to inhibit cell
proliferation in the animal tumor model and in some human
cancer cell lines. We have shown that EGCG inhibits the
expression of the PKC-α gene, adenosine kinase and type I
β cGMP-dependent protein kinase in LNCaP cells and hence is able
to block the intracellular cyclic-nucleotide signaling cascade[90].
The loss of tumor suppressor genes and the genes
producing anti-growth factors is an important event in cancer
development. Studies have shown that EGCG induces the
expression of 16 kinases and phosphatase genes in prostate
cells. These include tumor suppressor gene SHP-1 and the
genes that produce pyrroline-5-carboxylate and prostatic acid
phosphatase. The p53 tumor suppressor gene is the most
frequently mutated gene found in human malignancies,
including cancer of the prostate gland. Generally, no
correlation between p53 mutation and early stage PCa has been
noticed but p53 mutations are shown to be associated with
10%_20% of advanced PCa patients with high Gleason grade
and distant site metastasis[91,92]. In a study from our
laboratory, we have shown that EGCG upregulated the
protein levels of p53 in LNCaP cells (with wild type p53) but not
in DU 145 cells (with mutant p53)[93]. Further, we have also
shown that EGCG-induced apoptosis in LNCaP cells occurs
through the stabilization of p53 protein via phosphorylation
on critical serine residues and p14ARF- mediated
downregula-tion of MDM2 protein[94].
Role of tea polyphenol on programmed cell death
(apoptosis) in PCa Morphologically, apoptosis is
characterized by a temporal sequence of events consisting of
chromatin aggregation, nuclear and cytoplasmic condensation, and
eventual fragmentation of the dying cell into a cluster of
membrane bound segments that often contain
morphologically intact organelles[95]. These apoptotic bodies are
rapidly recognized, phagocitized, and digested by either
macrophages or adjacent epithelial
cells[96]. The hallmark of apoptosis is the fragmentation of genomic DNA, an
irreversible event that commits the cell to die and occurs before
changes in plasma and internal membrane
permeability[97]. In addition, apoptosis is a discrete way of cell death that is
different from necrotic cell death and regarded to be an ideal
method of cell elimination[98]. Under normal cellular
situations a balance between cell growth and cell death is
main-tained, this balance is lost in favor of cell growth in the case
of cancers including cancer of the prostate gland.
Correction of this imbalance could lead to the prevention and even
ablation of prostatic cancer[99,100] as apoptosis is closely
involved in the initiation, progression, and metastasis of
human PCa. Since human PCa represents a heterogeneous
mixture of androgen-dependent and androgen-independent
mixture of cells, the surgery and chemotherapy have failed to
address this problem. Hence, one potential strategy to
eradicate this mixture of cells is to modulate the apoptotic
machinery by chemopreventive agents. Chemopreventive
agents, which can modulate apoptosis, may be able to affect
the steady-state cell population that can be useful in the
management and therapy of cancer. Many cancer
chemopre-ventive agents have been shown to induce apoptosis and
conversely several tumor promoters have also been shown
to inhibit apoptosis[101_103]. Therefore, it is reasonable to
assume that the chemopreventive agents that have proven
effects in animal tumor bioassay systems and/or human
epidemiology on one hand and cause induction of apoptosis of
cancer cells on the other hand may have wider implications
for cancer control. Studies from this and other laboratories
have shown that EGCG results in an induction of apoptosis
in several human carcinoma
cells[39,93,104]. A study from our laboratory has demonstrated that green tea constituent EGCG
results in an induction of apoptosis in human PCa cells
LNCaP and DU145[93]. This observation was subsequently
verified by the studies from another
labratory[105]. We
recently demonstrated that EGCG-induced apoptosis in
human prostate carcinoma LNCaP cells is mediated via
modulation of two related pathways: (1) stabilization of p53 and
down regulation of MDM2 protein; and (2) negative
regulation of NK-κB activity, thereby, decreasing the expression
of the pro-apoptotic protein Bcl-2[94].
Role of tea polyphenols on angiogenesis in PCa
Cancer cells move from their original sites and invade surrounding
tissues, a phenomenon known as `metastasis'. Metastasis
is subsequently followed by the formation of new blood
vessels, a phenomenon known as `angiogenesis', a major
event of later stages of carcinogenesis. Some hydrolases
and matrix metalloproteases (MMPs) have been
reported to be overexpressed during the invasion of cancer cells and
angiogenesis[106,107]. Once tumors become aggressive and
start to metastasize to other organs, even systemic
chemotherapy may be futile. Garbisa et
al[108] reported that EGCG is a potent inhibitor of gelatinases and an orally available
pharmacologic agent that may confer the antiangiogenic and
antimetastatic activity associated with green tea. EGCG was
also found to inhibit tumor cell invasion and directly
suppress the activity of two matrix metalloproteases, MMP2 and
MMP9, most frequently overexpressed in cancer and
angiogenesis and essential in penetrating the basement membrane
barriers[109_111]. Recently we showed that green tea infusion
in the TRAMP mice resulted in marked inhibition of the
markers of angiogenesis and metastasis most notably vascular
endothelial growth factor (VEGF), urokinase plasminogen
activator (uPA), and MMPs 2 and 9[112]. It has been shown
that tea components slow the progression of LNCaP human
prostate tumors in SCID mice, partly by inhibiting the
formation of new blood vessels[113]. A recent study investigated
the effect of EGCG on the tube formation of human umbilical
vein endothelial cells (HUVEC) on matrigel. Tube formation
was inhibited by treatment both prior to plating and after
plating endothelial cells on matrigel with EGCG. EGCG
treatment also was found to reduce the migration of endothelial
cells in a matrigel plug model. These findings suggest that
EGCG also acts as an angiogenesis inhibitor by modulating
protease activity during endothelial
morphogenesis[110].
Role of tea polyphenols on Insulin like growth factor in
PCa Studies established that elevated circulating levels of
Insulin-like growth factor 1 (IGF-1) are associated with
increased risk of several common cancers, including those
of the breast, prostate, lung and
colorectum[114]. IGF-1 has mitogenic and anti-apoptotic effects on prostate epithelial
cells in vitro and has been strongly implicated in the
etiology of human PCa. The level of IGF-binding protein 3
(IGFBP-3), a major IGF-1 binding protein in serum that, in most
situations, suppresses the mitogenic action of IGF-1, has
been shown to be inversely associated with the risk of
different cancers[115]. The elevated level of IGF-1 with
concomitant lowering of IGFBP-3 in serum is an excellent
predictor of PCa progression in humans. The identification of
agents that can inhibit the IGF-1 signaling pathway could
lead to the development of highly successful prevention
strategies for PCa. IGF-1 has been implicated as an
important factor in the initiation and progression of PCa in a
TRAMP model[116], and we have shown that oral infusion of
GTP significantly lowers IGF-1 levels and restores the
depleted levels of IGFBP-3 in the serum of TRAMP
mice[55]. In a study, we demonstrated that the IGF-1/IGFBP-3
signaling pathway is a prime pathway for GTP-mediated inhibition
of PCa that limits the progression of cancer through
inhibition of angiogenesis and
metastasis[112].
Regulation of cell cycle in prostate cancer cells by tea
polyphenols The mammalian cell division cycle is a set of
events that governs the self-replication of cells. Normal cell
growth and division depends on precise regulation of cell
cycle; the loss of which can result in unrestrained cell division.
The consequence of this includes cell proliferation,
tumorigenesis and cancer. A controlled cell cycle progression is
important and essential for normal tissue
homeostasis[98]. Cell cycle progression is monitored by surveillance
mechanisms, or cell cycle checkpoints, that ensure initiation
of a later event is coupled to the completion of an early cell
cycle event. One or more cell-cycle checkpoint defects are
involved in most of the cancer types including
PCa[93,117,118]. A normal cell cycle progression is dependent on the ability
of the cell to translate extracellular signals, such as
mitogenic stimuli and intact extracellular matrices in order to
efficiently replicate DNA and divide. The cell cycle progression
is controlled by kinase complexes consisting of a
cyclin-dependent kinase (Cdk) subunit and a cyclin subunit. Cdk
respond to the extracellular signals and push cells through
the cell cycle. Transitions between different phases in the
cell cycle are driven by sequential activation and
inactivation of various Cdk in complexes with cyclins. Abnormal
Cdk activity is accomplished by cyclin amplification, cdk or
substrate mutation as well as inactivation of inhibitors such
as WAF1/p21, INK4a/p16, and
INK4c/p18[120]. The selective growth advantage of cancer cells also stems from the
amplification of positive growth signals and mutation of
checkpoints. The loss of cell cycle checkpoints results in
the selection of cells that have a growth advantage that may
result in drug resistance, invasion and
metastasis[121]. Also, inhibition of the cell cycle has been appreciated as a target
for the management of cancer[122]. A few reviews are
available that contain information about the dysregulation of cell
cycle in prostate
carcinogenesis[118,119]. Tea polyphenols have
been shown to impart cell cycle arrest in cancer cells via
inducing the expression of cdk
inhibitors[123]. Earlier, our laboratory showed that EGCG exhibited a dose-dependent
arrest of cells in G0/G1 phase of the cell cycle, thereby
slowing the growth of human PCa
cells[93]. Recently, we elucidated the molecular mechanism involved in the cell cycle
arrest in human PCa cells[123]. Our data demonstrated that
EGCG treatment of LNCaP and DU-145 cells resulted in
significant dose- and time-dependent (1) upregulation of the
protein levels of WAF1/p21, INK4a/p16, and INK4c/p18; (2)
down-modulation of the protein levels of cyclin D1, cyclin E,
cdk2, cdk4, and cdk6, but not of cyclin D2; and (3) increase
in the binding of cyclin E toward cdk2. This resulted in a
blockade of G1 to S transition, causing a G0/G1 phase arrest
of the cell cycle. The effect of EGCG on the interbinding
between the different components of the cki-cyclin-cdk
network, however, needs further investigation.
Modulation of phosphatidylinositol-3-kinase/protein
kinase B and mitogen activated protein kinases by
tea Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB)
and MAPK signaling pathways are regarded to play a
critical role in cellular proliferation, cell cycle regulation and
apoptosis. Defects in these signaling pathways have been
found to result in the development of various cancer
types[124]. PI3K catalyzes the formation of the 3'-phosphoinositides,
phosphatidylinositol 3,4-diphosphate and
phosphatidy-linositol 3,4,5-triphosphate. An increase in
3'-phosphoino-sitides leads to membrane translocation of downstream
effectors such as the serine/threonine protein kinase Akt,
resulting in increased cellular proliferation and protection
from apoptosis[125]. The MAPK family such as extracellular
signal regulated protein kinase (Erk) 1 and 2 are shown to be
constitutively active in PCa in humans, and possibly play a
causative role in the progression of this malignancy from an
androgen-sensitive phenotype to an advanced and
androgen-insensitive metastatic disease. It has been shown that
the activation of MAPK by green tea might be a potential
mechanism in the regulation of antioxidant-responsive
element mediated phase II enzyme gene
expression[126]. In one report, the authors found that GTP causes a significant
activation of extracellular signal-regulated kinase 2 (ERK2) and
c-Jun N-terminal kinase 1 (JNK1)[126]. GTP treatment also
resulted in increased mRNA levels of the immediate-early
genes c-jun and c-fos, as determined by reverse
transcriptase-coupled polymerase chain
reaction[126]. Exposure of normal human epidermal keratinocytes (NHEK) to UVB
radiation induces oxidative stress and phosphorylation of
MAPK. Studies from this laboratory have shown that
pretreatment of normal NHEK with EGCG inhibits UVB-induced H2O2 production and
H2O2-mediated phosphorylation of
MAPK[127].
We recently evaluated the effects of EGCG and TF, on
PI3K- and MAPK-pathways in DU145 and LNCaP cells. Both
EGCG and TF treatment were found to (1) decrease the levels
of PI3K and phospho-Akt; and (2) increase Erk1/2 in both
DU145 and LNCaP cells. This study, for the first time,
demonstrated the modulation of the constitutive activation of
PI3K/Akt and Erk1/2 pathways by EGCG as well as
TF[124]. More recently an in vivo
study revealed that oral infusion of GTP resulted in significant decrease in (1) the protein
levels of PI3K; (2) phosphorylation of Akt; and (3)
phosphorylation of ERK1/2 in TRAMP[112].
Modulation of nuclear factor κB by EGCG The nuclear
transcription factor NF-κB plays an important role in
inflammation, autoimmune response, cell proliferation and
apoptosis by regulating the expression of genes involved in
these processes and thus, is widely recognized as a critical
mediator of immune and inflammatory responses.
Constitutive activation of the transcription factor
NF-κB has been observed in a high proportion of androgen-independent
PCa[128_130]. In addition to suppressing apoptosis,
NF-κB promotes malignant behavior in other ways like stimulating
transcription of cell cycle progression factors (c-myc, cyclin D1),
proteolytic enzymes (MMP-9, uPA), and angiogenic factors
VEGF and IL-8[130,131]. Thus, it is not surprising that nuclear
localization of NF-κB in PCa biopsies has been shown to
correlate with poor clinical
prognosis[132]. A mystifying array of natural products, some of which have putative
chemo-preventive activity, are reported to inhibit constitutive
and/or stimulated NF-κB activity in human PCa. In a study, we
demonstrated that EGCG treatment to normal NHEK keratinocytes resulted in a significant dose- and time-dependent inhibition of UVB-mediated activation and nuclear
translocation of a NF-κB/p65, suggesting that that EGCG
protects against the adverse effects of UV radiation via
modulations in the NF-κB pathway[46]. In another study from our
laboratory, it was demonstrated that EGCG had a concurrent
effect on p53 and NF-κB, causing a change in Bax/Bcl-2 ratio
in a way that favors apoptosis in prostate carcinoma LNCaP
cells[94].
Effects of tea and its polyphenols on prostate tumor
xenografts Athymic nude mice implanted with tumor
xenografts have been widely used as an established
pre-clinical in vivo model to assess the effect of drugs and/or
synthetic agents and dietary substances on the
development of a variety of cancer types. Liao and
colleagues[133] studied the effects of tea polyphenols on growth inhibition
and regression of prostate tumors in athymic nude mice.
They found that intraperitoneal injection of EGCG but not
structurally related catechins, such as ECG, inhibited the
growth and rapidly reduced the size of human prostate PC-3
(androgen-insensitive) and LNCaP 104-R (androgen-repressed) tumors. In a recent
study[134], we demonstrated that GTP, black tea extract (BTE), EGCG and TF resulted in
significant inhibition in the growth of androgen responsive
CWR22Rn1 implanted tumors in athymic nude mice. Further,
treatment of mice with all tea preparations resulted in
significantly reduced PSA secretion in serum measured at 3 and 4
weeks post implantation of CWR22Rn1 cells.
The immuno-blot analyses of the tumors revealed that the prostate tumor
growth inhibitory response of all tea preparations was
accompanied with (1) decrease in Bcl-2 (anti-apoptotic) with
a concomitant increase in Bax (pro-apoptotic); (2) activation
of Caspase-3; (3) cleavage of PARP; and (4) decrease in VEGF.
This study suggested that GTP and BTE as well as their
major polyphenolic constituents EGCG and TF significantly
inhibited the development of PCa via (1) induction of
apoptosis; and (2) inhibition of angiogenesis in tumors.
Furthermore, in an independent experiment, we found that
GTP, at very low doses (0.1% and 0.05% in water) resulted in
a significant regression of tumors in athymic nude mice when
given after CWR22Rn1 tumors were established to a volume
of approximately 400 mm3. These data point to a potential
therapeutic benefit of black as well as green tea against PCa.
Custom tailoring of chemopreventive regimen for prostate cancer
Cancer is the result of several genetic mutations, which
in turn results in defects in multiple signaling pathways
being affected. It is therefore unlikely that any single agent
may prove to be totally effective and/or beneficial for PCa
prevention or treatment in all populations on a long-term
basis. We recently advocated the idea of combining
naturally occurring agents in a manner that could be more
beneficial and at the same time would not exhibit toxicity. It is of
interest that several dietary agents that are effective
chemopreventive agents in one experimental setting can
enhance or have no effects on carcinogenesis in another
experimental setting. Thus it is likely that we can custom
tailor or personalize the chemopreventive regimen through a
cocktail of agents with agents that have known mechanisms
targeted for different individual needs. This concept of
combining chemopreventive agents to achieve greater benefits
is being increasingly appreciated and studies are being
conducted in our and other laboratories using a combination of
natural agents and chemotherapeutic drugs. To achieve the
objective, there is also a need to understand genetic,
environmental, and lifestyle factors that influence various
populations for whom the chemoprevention intervention is
considered. This information could be critical in the
selection of an appropriate cancer chemopreventive regimen for
individuals with varying risk for PCa development. A
combination of different nutraceuticals with varied mechanisms of
action could be more effective as they could attack process
of carcinogenesis at more than one site or pathway(s) and
result in the treatment having an additive or synergistic
effect against cancer growth and development. We recently
demonstrated the combined inhibitory effects of green tea
polyphenols and COX-2 inhibitor on growth of PCa
cells in in-vivo and in-vitro
situations[135]. This study reported an
increased efficacy of selective COX-2 inhibitors in
combination with polyphenols from green tea for inhibition of growth
of human prostate cancer cells both in vitro
and in vivo. A recent study demonstrated that combined treatment with
lycopene and vitamin E, at 5 mg/kg BW each, suppressed
orthotropic growth of PC-346C prostate tumors by 73% and
increased median survival time by
40%[136]. In another study, Venkateswaran
et al. demonstrated that selenium
potentiates vitamin E-induced inhibition of LNCaP cells and this
inhibition was demonstrated by a reduction of cells in the
S-phase of cell cycle[137]. A study by Tokar
et al[138] examined the effects of synthetic retinoid
N-(4-hydroxyphenyl)retinamide (4-HPR) in combination with cholecalciferol
(vitamin D3) on growth, and on the expression of vimentin,
matrix metalloproteinase-2 (MMP-2), and retinoid and
vitamin D receptor expression, using the non-tumorigenic,
human prostate epithelial cell line RWPE-1. These results
suggested that combined treatment with 4-HPR and
cholecal-ciferol, at doses lower than what might be effective with
single agents, increase anti-cancer efficacy.
In light of the observations suggesting more beneficial
effects with a combination of chemopreventive agents at
low doses, we advocate to design experiments containing a
mixture of substances that target multiple signaling pathways.
Epidemiological studies
In recent years, the availability of increasingly
sophisticated biochemical approaches of molecular epidemiology has
made the process of cancer formation easier to understand
and comprehend. Such understanding has offered
opportunities for defining the risk to individuals and for modulating
this risk by means of agents that can alter critical steps in the
multistage process of carcinogenesis. As of yet, only a few
case control studies have been conducted to evaluate the
effect of consumption of tea for human PCa. All published
data seeking an association between tea consumption and
the risk of PCa considered undefined tea preparations, mostly
black tea. The possible harmful effects of excessive tea
consumption, tea consumption at very high temperature, or
the consumption of salted tea had not been yet ruled out.
Two epidemiological studies have shown that people who
regularly consume tea have a lower incidence of
PCa[139,140]. Heilbrun et
al[139], in a prospective cohort study of 7833 men
living in Hawaii with Japanese ancestry, observed a weak
but significant negative association between black tea
intake (more than one cup per day) and PCa incidence
(P=0.02). In a case-control study conducted in 3 geographical
areas of Canada, Jain et al[140] observed a decrease in PCa
risk with an intake of more than 2 cups of tea per day. Other
epidemiological studies conducted in
Italy[141], Utah[142] and
Canada[143] did not find any difference of risk for PCa
between tea drinkers and non-drinkers. It should be noted that
most of these studies lacked appropriate
controls for comparison in categorization of tea consumption, the type of tea
consumed and the ethnicity of the subjects, which weakens
the overall effect of the study.
Recently, to investigate whether green tea consumption
has an etiological association with PCa, a case-control study
was conducted in Hangzhou, southeast China during
2001_2002[144]. In this study, 130 incident patients with
histologically confirmed adenocarcinoma of the prostate and 274
hospital inpatients without PCa or any other malignant diseases
and matched to the age of cases were monitored.
Information on duration, quantity and frequency of usual tea
consumption, as well as the number of new batches brewed
per day, were collected by face-to-face interview using a
structured questionnaire. The risk of PCa for tea
consumption was assessed using multivariate logistic regression
adjusting for age, locality, education, income, body mass index,
physical activity, alcohol consumption, tobacco smoking,
total fat intake, marital status, age at marriage, number of
children, history of vasectomy and family history of PCa.
Among the cases, 55.4% were tea drinkers compared to
79.9% for the controls and almost all the tea consumed was green
tea. The PCa risk was found to be declined with increasing
frequency, duration and quantity of green tea consumption.
The dose response relationships were also significant,
suggesting that green tea imparts chemopreventive effects
against PCa in humans[144].
Clinical trials with green tea
A phase I trial of green tea extract in patients with solid
tumors was conducted to ascertain the maximum
tolerated dose, toxicity, and pharmacology of oral green tea extract.
This study concluded that 1.0 g/m2 of green tea extract three
times a day [equivalent to 7 to 8 Japanese cups (120 mL) of
green tea] is well tolerated and is not associated with any
side effects[145]. One recent phase II clinical trial explored the
anti-neoplastic effects of green tea in patients with
metastatic androgen-independent
PCa[146]. In this study, forty-eight patients were instructed to take 6 g of green tea per day
orally in 6 divided doses. Results from this study showed
that only one patient within this 42-patient cohort manifested
a 50% decline in PSA values from baseline, but this
reduction was not sustained beyond 2 months. Although green
tea was tolerated well, a notable percentage of patients
experienced adverse effects such as insomnia, fatigue etc.,
presumably from caffeine present in the tea. It should however,
be noted that this study was conducted in patients with
metastatic androgen-independent PCa and therefore, in
principle, is not a representation of the chemopreventive
effects of green tea. Furthermore, the median time on this
study was only one month, whereas, prior pre-clinical data
have been suggesting that green tea requires prolonged
exposure to exert its antitumor
activity[110,112]. Taken into consideration the drawbacks of this trial, the negative findings
of this study do not contradict the results of earlier
epidemiological studies, which suggest that green tea may confer
antitumor effects in a relatively healthy population. Thus,
for an ideal prospective study, a population with high risk
for PCa development should be considered and the length
of exposure of green tea to the subjects should be taken into
consideration.
Bettuzzi et al[147] recently carried out a one-year
proof-of-principle clinical trial to assess the safety and efficacy of
GTCs for the chemoprevention of CaP in high-grade
prostate intraepithelial neoplasia (HG-PIN) volunteers. Sixty
volunteers with HG-PIN, were enrolled in this double-blind,
placebo-controlled study. Daily treatment consisted of three
GTCs capsules, 200 mg each (total 600 mg/d). After one
year, only one tumor was diagnosed among the 30
GTC-treated men (incidence, approximately 3%), whereas nine
cancers were found among the 30 placebo-treated men
(incidence, 30%). Total prostate-specific antigen did not
change significantly between the two arms, but GTCs-treated
men showed values constantly lower with respect to
placebo-treated ones. International Prostate Symptom Score
and quality of life scores of GTC-treated men with coexistent
benign prostate hyperplasia (BPH) improved, reaching
statistical significance in the case of the International Prostate
Symptom Scores. No significant side effects or adverse
effects were documented. This is the first study showing that
GTCs are safe and very effective for treating premalignant
lesions before PCa develops. As a secondary observation,
administration of GTCs was also found to reduce lower
urinary tract symptoms, suggesting that these compounds might
also be of help for treating the symptoms of BPH.
Confirmation of these findings in another group of patients is awaited.
Conclusion and future perspectives
Prostate cancer exists in either a latent, clinically
insignificant form or in an aggressive form that progresses to
various other body sites. Moreover, it is a complicated
malignancy with tremendous heterogenicity of
androgen-dependent and androgen-independent forms and because of
the co-existence of multiple pathological entities, it has not
been possible to provide satisfactory treatment options for
this disease. Thus, chemoprevention with a naturally
occurring non-toxic agent such as green tea could be useful in the
management of this disease.
Recent pre-clinical studies have shown that tea and its
constituents inhibit cell cycle, induce apoptosis and
modulate multiple signaling pathways in a fashion that
encourages the elimination of precancerous and cancerous cells.
The uniqueness of the action of tea perhaps lies in its
specificity of killing cancer cells without affecting the growth of
normal cells. Although studies on tea polyphenols
demonstrate its efficacy as a potent chemopreventive agent against
PCa, there are still many gaps in our current awareness. There
are certain factors such as bio-availability, tissue level of tea
constituents, tea type, drinking habit, race,
etc. that need to be taken care of before a recommendation could be made for
tea polyphenols as preventive or therapeutic agent for
human use. The bio-availability of the active polyphenolic
constituents after tea consumption by laboratory animals
and humans is poorly defined. Yang et al and
others[148_150] have measured the concentration of tea polyphenols in
human plasma, saliva, feces and urine after consuming
decaf-feinated green tea and found that EGCG was in lesser
concentration than EGC. Therefore, a great deal of laboratory
research and many more epidemiological studies are needed
for obtaining conclusive evidence. The increase or decrease
of PSA and IGF-1 and IGFBP3 in relation to tea consumption
and levels of tea polyphenols in urine samples may be used
as biomarkers in PCa chemoprevention. This type of study
could answer the question of how much tea should be
consumed by humans for PCa chemoprevention and explain the
mechanism involved.
Prostate cancer is a disease of many etiological factors
and involves several mechanisms in its progression.
There-fore, the modulation of a single mechanism alone may not
completely impede the progression of PCa. Therefore, a
strategy of acting on multiple signaling pathways using a
combination of chemopreventive agents should be explored for
PCa chemoprevention in pre-clinical studies. For such a
type of combination chemoprevention strategy, the agents
should be selected based on their mechanism of action in
such a way that two or more signaling pathways are attacked
with two or more agents to impart a synergistic response
against PCa. Because of the promising effects of tea
consumption on tumor induction in animals and in a case
control study, we recommend that this effect should be
examined in a large population.
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