Tea (Camellia sinensis (L.)): A Putative Anticancer Agent in Bladder Carcinoma?

Abstract

The leaves of Camellia sinensis (L.) are the source of tea, the second most consumed beverage worldwide. Tea contains several chemical compounds such as polyphenols (mainly catechins), caffeine, theophylline, L-theanine, among many others. Polyphenolic compounds are mainly responsible for its significant antioxidant properties and anticarcinogenic potential. Bladder cancer is one of the most common types of cancer, and its progression and onset are thought to be controlled by dietary and lifestyle factors. Epidemiological studies showed that the regular consumption of tea can be a preventive factor for this type of cancer, and several in vivo and in vitro studies reported that tea and its components may interfere in the cancer cells' signaling, preventing the bladder tumor progression. The mechanisms responsible for this protection include deregulation of cell cycle, induction of apoptosis while protecting the surrounding healthy bladder cells, inhibition of metastization processes, among others. Herein, we discuss the potential beneficial effects of tea and tea components in bladder cancer prevention and/or treatment, and how they can be helpful in finding new therapeutic strategies to treat this type of cancer.

Full text

Send Ord ers for R eprints to reprints@benthamscience.net
26 Anti-Cancer Agents in Medicinal Chemistry, 2015, 15, 26-36
Tea (Camellia sinensis (L.)): A Putative Anticancer Agent in Bladder Carcinoma?
Vanessa R. Conde, Marco G. Alves#, Pedro F. Oliveira and Branca M. Silva#,*
CICS – UBI – Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã,
Portugal
Abstract: The leaves of Camellia sinensis (L.) are the source of tea, the second most consumed beverage
worldwide. Tea contains several chemical compounds such as polyphenols (mainly catechins), caffeine,
theophylline, L-theanine, among many others. Polyphenolic compounds are mainly responsible for its significant
antioxidant properties and anticarcinogenic potential. Bladder cancer is one of the most common types of cancer,
and its progression and onset are thought to be controlled by dietary and lifestyle factors. Epidemiological
studies showed that the regular consumption of tea can be a preventive factor for this type of cancer, and several in vivo and in vitro
studies reported that tea and its components may interfere in the cancer cells’ signaling, preventing the bladder tumor progression. The
mechanisms responsible for this protection include deregulation of cell cycle, induction of apoptosis while protecting the surrounding
healthy bladder cells, inhibition of metastization processes, among others. Herein, we discuss the potential beneficial effects of tea and
tea components in bladder cancer prevention and/or treatment, and how they can be helpful in finding new therapeutic strategies to treat
this type of cancer.
Keywords: Bladder cancer, caffeine, Camellia sinensis, catechins, EGCG, polyphenols.
#Author’s P rofile: Marco G. Alves, PhD in Biochemistry, at University of Coimbra, Portugal (2011), mainly works on reproduction,
diabetes, metabolic modulation and cellular metabolic profiles. He serves as editorial board member and ad-hoc reviewer in several journals.
He has more than 55 publications in the last years (2009-2014) in leading peer-review journals.
#Author’s Profile: Branca M. Silva is Associate Professor at University of Beira Interior (Portugal) since 2011. Presently, she is author/co-
author of about 60 publications in peer-review journals, and her research interests are oriented to the Phytochemistry and Phytomedicine
fields. She serves as editor-in-chief, editor, editorial board member and reviewer in several journals.
INTRODUCTION
Camellia sinensis (L.), commonly known as the tea plant, has
been used for many centuries in traditional medicine. The infusion
prepared by using its leaves or buds is known as tea. The main
types of tea obtained from this plant are green tea (GT), white tea
(WT), black tea (BT) and oolong tea (OT). This classification is
based on differences in the manufacture and preparation processes,
which result in distinctive chemical compositions. Recently, tea’s
ability to stimulate the immune system and mitigate several
diseases has raised great interest [1-10], and these beneficial
properties have been attributed to its chemical composition.
Cancer constitutes one of the greatest challenges in terms of
developing preventive, therapeutic and diagnosis methods [11].
Phytomedicine is now considered a h elpful research area for
battling this burden [12-14]. In this context, chemopreventive and
chemotherapeutic properties of tea have been studied, and new data
arise to unveil the molecular mechanisms by which tea and its
components exert their actions. Bladder cancer is among the most
common types of cancer and it can appear under different forms,
being the transitional cell carcinoma (TCC) the most frequent [15,
16]. The majority of TCC tumors are superficial papillary tumors,
and only 10 to 15% of the cases evolve to a much more aggressive
non-papillary phenotype, that invades the muscle wall of the
bladder (for review see [15]). In 2008, nearly 400.000 new cases
and 150.000 deaths were estimated due to this type of cancer, that
most frequently affects men [17].
Many factors are pointed out as risk factors for the development
of this disease (for review see [15]). These include smoking [16, 18,
19], exposure to diesel and combustion fumes [18], genetic components
account the widely accepted health benefits of tea, studying its
*Address correspondence to this author at the Health Sciences Research
Centre, Faculty of Health Sciences, University of Beira Interior, Av. Infante
D. Henrique, 6201-506 Covilhã, Portugal; Tel: +351 275 329077;
Fax: +351 275 329099; E-mail: bmcms@ubi.pt
[16, 18, 20] and liquid ingestion [20, 21]. Of note, it has been
reported that the consumption of milk [21], BT, GT [20] and some
alcoholic beverages [20, 21], decreases the risk of developing
bladder cancer. This type of cancer is thought to be preventable by
modification of dietary factors [22]. Therefore, and having in
effects on bladder cancer can yield new insights on the treatment
and prevention of this disease. Herein, we present an up-to-date
overview of the potential beneficial effects of tea and its components
in the prevention and treatment of bladder cancer.
CLASSIFICATION OF TEAS
Tea is one of the most popular beverages worldwide and is
produced by infusion of the leaves or buds of the tea plant
(Camellia sinensis). This beverage has been used in eastern
traditional medicine for many centuries, since it yields several
health benefits [4, 9, 23]. C. sinensis can originate four major types
of tea, depending on the tea leaves’ harvesting and processing [4, 9,
23]. Upon harvesting, the leaves suffer an enzymatic oxidation
process, also called “fermentation” [4, 9]. The enzyme involved in
this process, polyphenol oxidase (PO), is mainly responsible for the
differences in the phenolic profiles of the several types of tea. Its
action can be inactivated by quickly heating the leaves or buds, a
post-harvesting technique commonly used in the production of GT
and WT [4, 9]. GT, BT and OT are all obtained from C. sinensis mature
dried leaves, but they possess different chemical compositions.
Consequently, some very obvious organoleptic differences, namely
in taste, color and flavor are also noted. In the production of GT
[24], the mature leaves are harvested and then quickly heated, to
inactivate PO and prevent oxidation. On the other hand, the
production of BT [25], includes crushing the leaves, which are then
allowed to “ferment” for two hours, and heated afterwards.
Production of OT is similar to the latter; however, the leaves are
only allowed to “ferment” for one hour before being heated [4, 9].
WT, the most expensive and rare type of tea, is produced from the
tips or leaf buds not fully opened, which are quickly heated to
prevent withering and oxidation [4, 9]. Thus, WT’s chemical
composition is similar to that of C. sinensis buds and young leaves.
187-5/15 $58.00+.00 © 2015 Bentham Science Publishers

Tea and Bladder Cancer Anti-Cancer Agents in Medici nal Chemistry, 2015, Vol. 15, No. 1 27
CHEMICAL COMPOSITION OF TEAS
Tea’s chemical composition is very complex, containing
polyphenols, proteins, polysaccharides, amino acids, minerals, trace
elements, methylxanthines and organic acids, among others [4, 9].
The chemical composition of tea may be affected by several factors
such as geographical origin, climate, growing conditions, harvesting
practices, maturity stage of the plant and manufacturing processes
[4, 9, 26].
Tea Cat echins
Polyphenols are the most abundant and active group of
compounds present in tea, and are thought to be the responsible for
much of the health benefits attributed to this beverage [6, 27, 28].
Flavonoids are amongst the major classes of phenolic compounds,
from which is important to highlight the flavan-3-ol family. The
members of this family are also known as catechins. There are
various catechins in tea, such as (-)-epicatechin (EC), (-)-
epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG ) and (-)-
epigallocatechin-3-gallate (EGCG) [9, 23]. These compounds are
thought to possess a very high antioxidant power [28-30].
The health benefits attributed to catechin s are mainly due to
their chemical stru cture. Catechins are essentially comprised of
three rings (the aromatic rings, A and B, linked to a dihydropyran
heterocyclic ring, C) and are characterized by multiple hydroxyl
groups on the A and B rings [31] (Fig. 1). Their chemical
differences are due to the presence of different groups attached to
those rings [4, 9, 31]. In EC, we can find an ortho-di-hydroxyl
group in the B ring and a hydroxyl group in the C; ECG, contains a
gallate moiety esterified in the C ring. EGC possesses a trihydroxyl
group on the B ring, and EGCG possesses an esterified gallate on
the C ring [4, 31]. GT and WT present higher catechin content,
while OT and BT possess in high quantities other phenolic
compounds [4, 25, 26, 32]. The enzyme PO, released during the
crushing of the leaves for production of BT and OT, catalyzes the
oxidation and polymerization of the catechins, producing theaflavins
and thearubigins [25, 26].
Theaflavins (Fig. 2) are comprised of the bicyclic benzotropolone
ring, and result o f the catechins’ d imerization. In turn, thearubigins
possess oligopolymeric structures and are thought to be the result of
the hydroxylation of theaflavins, but are still poorly chemically
characterized.
Fig. (2). Chemical structures of the main theaflavins. Theaflavins result from
the dimerization of catechins and are constituted by a skeleton comprised of
the bicyclic benzotropolone ring . The majority of theaflavins are formed from
an epicatechin and an epigallocatechin. Theaflavin-3,3’-digallate is produced
by dimerization of epicatechin-3-gallate and epigallocatechin-3-gallate.
Fig. (1). Chemical structures of the main tea catechins. These compounds are mainly constituted by two aromatic rings (A, B) and a dihydropyran heterocyclic ring (C).
The flavan-3-ol epicatechin is constituted by an ortho-di-hydroxyl group in the B ring (at carbons 3’ and 4’) and a hydroxyl group in the C ring (at carbon 3), and its
ester derivative epicatechin-3-gallate possesses an additional gallate moiety esterified in the C ring, at carbon 3. Epigallocatechin contains three hydroxyl groups in
the B ring (at carbons 3’, 4’ and 5’) and its ester derivative epigallocatechin-3-gallate additionally possesses an esterified gallate at the carbon 3 of the C ring.
7
65
8
4
3
2
O
1
1' 6'
5'
4'
3'
2'
OR2
HO
OH
OH
OH
R1
OH
OH
OH
C
O
O
AC
B
Main catechin structure
Gallate group
R1 R2
(-)-epicatechin H H
(-)-epigallocatechin OH H
(-)-epicatechin-3-gallate HGallate group
(-)-epigallocatechin-3-gallate OH Gallate group
O
OH
HO
OR
O
OH
OH
OH
OHO
OH
OR
R
Theaflavin H
Theaflavin-3,3'-digallate Gallate group

28 Anti-Cancer Ag ents in Medicinal Chemistry, 2015, Vol. 15, No. 1 Conde et al.
The chemical structure of tea’s components is particularly
associated with its antioxidant properties. Studies suggested a
relationship between the content of pyrogallol and hydroxyl groups
and the superoxide anion scavenging ability, as well as between the
presence of galloyl moieties and the ability to quench hydroxyl
radicals [9, 33]. Also, the number and position of the hydroxyl
groups on the molecules influences the antioxidant ability of
flavonoids [31]. Tea catechins such as EGCG lack a 2, 3 double
bond and a carbonyl group at the 4-position, a combination that
strengthens the antioxidant activity [9]. However, the higher total
phenolic component may not always be correlated with greater
antioxidant capacity, mainly because different phenolic profiles can
yield different responses [34]. OT and BT have a lower catechin
concentration but they are also important sources of health
promoting substances and have considerable antioxidant properties.
An analysis of commercial tea extracts showed that BT and OT
may have great importance in processes such as hydroxyl radical
scavenging and nitric oxide suppressing [26].
Among the most important contributions of tea to health are
its antioxidant [4, 7, 23, 35], anti-inflammatory, antimicrobial,
antimutagenic, antimetastatic and anticarcinogenic activities [4, 8,
10, 23, 35-39]. Moreover, studies suggested that regular tea intake
is potentially helpful in protecting against many chronic diseases,
such as cancer, and in enhancing the immune function [1, 6, 23, 27].
Among the tea catechins, EGCG is considered the most abundant
and active [4, 9, 23, 27, 40], and its beneficial effects have been
widely studied. Its anticancer potential has been reported as one of
its most important properties [35, 38, 41-47]. Nevertheless, aside
from the polyphenolic content, there are other tea components that
are thought to contribute to the improvement of health associated
with tea consumption. Caffeine, L-ascorbic acid, L-theanine,
quercetin, among others, may be crucial for the beneficial effects
attributed to tea consumption [4, 9, 48].
Tea Methylxanthines
Caffeine (Fig. 3) is the main methylxanthine present in tea
(ranging between 1.0% and 3.5% in tea preparations [26, 40]).
Other methylxanthines present in tea are theophylline and
theobromine.
Fig. (3). Chemical structure of caffeine (1,3,7-trimethylpurine-2,6-dione). It
is a naturally occurring tea purine derivative with th ree methyl groups at
positions 1, 3 and 7.
Of note, caffeine is one of the most consumed substances in the
world [49]. Tea is thought to be the second major source of caffeine
in the diet of North American adult population [50]. Due to its
chemical stability , caffeine levels in tea are not altered by
“fermentation” [25]. Still, the levels of caffeine present in each tea
type remains a matter of debate [26, 32, 51]. The discrepancies may
be due to different extraction conditions, distinct analytical methods
and the variability of the plants.
There are many adverse effects associated with excessive
caffeine consumption (for review, see [50]). Studies reported death
provoked by excessive intake of caffeine, although it is rare [50]. It
was proposed that reducing the caffeine content in GT may help to
highlight its beneficial properties for human health [52]. Similarly
to tea catechins, caffeine also has different effects at cellular and
metabolic levels (for review, see [53]). Its most important
mechanism of action involves selectively blocking the adenosine
receptors and competitively inhibiting the action of adenosine in the
cells, resulting in an increased release of hormones such as
norepinephrine, dopamine and serotonin [50].
Caffeine’s anticarcinogenic properties were also documented. A
study reported apoptosis induction after the topical application of
caffeine in skin tumors in rats, with virtually no effects on normal
tissue cells. The mechanisms were most likely p53 independent,
since the tumor cells displayed p53 mutations [54]. Others
suggested that this compound promotes cell cycle arrest in the
G0/G1 phase in cancer cells, most likely through suppression of
cyclin D1-cdk4 complex activation and consequent inhibition of
retinoblastoma protein (pRb) phosphorylation, in a dose-dependent
manner, suppressing the tumor proliferation without inducing cell
apoptosis [49]. Particularly in studies of tea consumption by
humans, the importance of caffeine in tea preparations was high lighted ,
since decaffeinated teas presented very low (or even inactive)
cancer inhibitory properties [5]. Besides, the intake of decaffeinated
coffee may be related with an increased risk for developing bladder
cancer [20]. However, data on the role of caffeine on tea-associated
health benefits are scarce and much work needs to be done.
TEA AND BLADDER CANCER
The manifestation of cancer is due to a large set of contributing
factors which makes it very difficult to identify th e exact causes,
biomarkers or treatments [16]. Although more studies are required,
especially regarding human bladder cancer, tea and its individual
components remain a field of interest in many studies [2, 3, 6, 35,
36, 39, 42, 46-48, 55-58]. Also, several studies reported that tea can
act against bladder cancer in different situations, as a preventive or
therapeutic factor. After GT ingestion by mice, tea catechins
(namely EGCG) can be widely distributed through the body but
they concentrate in specific organs, particularly in the bladder [36].
However, the anticarcinogenic properties of tea in human bladder
cancer, although predictable, still lack strong supporting evidence.
It was reported, by a number of studies, the beneficial role of tea
as a protective or preventive factor against this disease in humans
[20, 59, 60].
The selected studies performed on this matter (Tab le 1) include
case-controls [18, 20, 21, 59, 61-65] and cohort studies [19, 22, 60,
66] and are mostly based on the statistical analysis of questionnaires
filled by patients or former patients, regarding their dietary and
lifestyle habits in the years anteceding the cancer onset. Some
studies suggested that regular tea consumption can be either a risk
factor for bladder cancer [64] or a preventive factor [20, 59, 60].
Other studies reported that tea consumption has no association with
the disease triggering, development or outcome [18, 19, 21, 22, 61-
63, 65, 66]. Although these studies are very important, there are
also some drawbacks to be considered. The use of questionnaires
makes the studies highly dependent on the subjects’ interpretation
or past memory raising doubt about the veracity, due to the
subjects’ forgetting or deliberately tampering the facts. Besides,
most of these studies also include a complicated analysis of data,
ranging from type and duration of the beverages consumed, fruit
and vegetable consumption, smoking status, among others. Of note,
some of the studies do not refer the type of tea investigated [18, 59-
61, 65], which hinders any association between consumption of one
tea type and bladder cancer development. Finally, most of the
analysis were performed in very different populations, which greatly
vary in terms of age, countries and habits, making very difficult the
extrapolation of results and conclusions.
Regarding animal model and in vitro studies, the conclusions
are more elucidating, although there is still work to be done. GT
showed some promising results in preventing and treating several
types of cancer, including bladder tumors, and its identification as a
key antimutagenic factor dates as far as 1985 [37]. Mainly acting
N
N
O
ON
N
H3C
CH3
CH3

Tea and Bladder Cancer Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 29
through its polyphenol components, particularly catechins, it was
demonstrated the GT ability to prevent the in itiation and growth of
bladder tumors in rats [43, 58, 67], inhibit bladder tumor development
and invasion in vitro (in some cases showing positive synergistic
effects with other substances) [43, 48] and protect normal bladder
cells, while killing the malignant ones [43, 46]. Although catechins
alone are a powerful tool to oppose cancer development, GT extract
and dried leaves are also very helpful and a practical way to treat
cancer. They possess numerous components with anticancer benefits,
being less expensive, widely available and safe [67]. However,
there is some controversy about its exact mechanisms of action
and effects. Several authors suggested that GT does not induce
morphological changes in cultured bladder cancer cells, acting
only through modification of matrix components for growth
inhibition [48], while others reported, in the same circumstances,
morphological alterations accompanied by apoptosis in cancerous
cells [43].
Despite BT’s lower concentration of catechins, a study in rats
with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced
bladder cancer that consumed BT instead of water for 40 weeks
reported a significant decrease of tumor volume, although GT
showed even more positive results [67]. Regarding studies focused
in consumption by humans, BT is one of the most studied types of tea
(see Table 1). A case-control study in 40 human bladder cancer patients
from southern Taiwan and 160 subjects that did not displayed
bladder cancer or any other urological disease, suggested that the
regular drinking of GT or BT for a period over 30 years may
increase the risk of bladder cancer [64]. In contrast, a population-
based case-control study in 1452 bladder cancer patients and 2434
control subjects from Iowa, reported a preventive/protective role in
the subjects that drank more than 5 five cups of “tea” per day.
Though the tea type was not specified, the authors highlighted that
it may be mostly BT, once it is thought to be the most consumed tea
in western countries [59]. It was also reported the probable
protective role of daily consumption of one or more cups of BT and
GT in a case-control study of 1007 human patients with confirmed
bladder cancer, without treatment previous to the study, and 1299
healthy control subjects [20]. However, most studies focused on tea
consumption found no significant association between consumption
of BT and bladder cancer in humans [21, 22, 62, 63, 66].
Regarding OT, there is not much information on bladder cancer
related studies. A case-control study of southern Taiwan patients
reported no significant association between daily OT consumption
and bladder cancer [64]. On the other hand, a study focused on
consumption of OT by rats with induced bladder cancer showed
that regular OT intake, instead of water, decreased the bladder
tumor volume [67].
Concerning WT, as far as we know, there are no available
studies on its effect on human bladder cancer patients. WT
possesses nearly the same components as GT, although in different
amounts. Thus, this type of tea is expected to present bladder cancer
related health benefits. Moreover, the action of WT against other
types of cancer is well documented [8], as well its superior
antioxidant properties comparing to other types of tea [1, 4, 7, 8].
Overall, although there is some controversy, most of the studies
suggested that tea and its phytochemical components may be a
good strategy to prevent and treat bladder cancer. Nevertheless,
more studies are n eeded to clarify the molecular mechanisms b y
which tea and its phytocomponents act.
MOLECULAR MECHANISMS IN CHEMOPREVENTION
AND THERAPY OF BLADDER CANCER
C. sinensis can be used to yield teas with remarkable health
promoting benefits. The chemopreventive and chemotherapeutic
potentials of this beverage are well documented, but tea can exert
Table 1. Epidemiological studies regarding regular tea consumption and human bladder cancer. The types of tea, studies and results o btained by
the authors are resumed.
Main Conclusions
Type of Tea Co nsumed
Risk factor
Protective or
preventive action
No associ ation
Main Outc omes
Population-
based cohort
GT [19] 
[19] na [19]
Case-control
GT [20, 21, 64]
BT [20, 21, 62-64]
OT [64]
Unspecified [18, 65]

[64]

[20]

[18, 21, 62, 63, 65]
 In patients that consumed GT or BT daily (1 cup or more), for a period over
30 years. [64]
 In patients with daily consumption of GT and BT (1 cup or more). [20]
na [18, 21, 62, 63, 65]
Cohort
GT [22]
BT [22, 66]
Unspecified [60]

[60]

[22, 66]
 In postmenopausal women who consumed more than 2 tea cups daily. [60]
na [22, 66]
Epidemiological studies
Population-based case-
control
Unspecified [59, 61] 
[59]

[61]
 In subjects with low fluid intake who consumed more than 5 tea cups per day.
[59]
na [61]
Legend: BT – Black tea; GT – Green tea; OT – Oolong tea;  - Reduced number of cases of bladder cancer;  - Increased number of cases of bladder cancer; na – No statistically
significant association. Superscript numbers are references as indicated in references section.

30 Anti-Cancer Ag ents in Medicinal Chemistry, 2015, Vol. 15, No. 1 Conde et al.
its anticancer effects through different mechanisms (for review see
[68]). Tea catechins and other components possess anticarcinogenic
properties that have been tested in vitro. However, the metabolism
of catechins may alter their function and/or bioavailability,
hampering its beneficial activities [69]. Tea components were also
proved to be promising chemopreventive agents in vivo. Nevertheless,
most of those mechanisms are not yet fully understood, and the
identification of the exact components that contribute to those
effects is far from being disclosed. Controversy aside, it is widely
accepted that tea components, particularly EGCG and other catechins,
are crucial for its ch emopreventive activity. Some pathways and
targets of tea and its components, to exert their anticarcinogenic
activities, were identified (Fig. 4). These studies were mainly
focused on their antioxidant activity or specific cell signaling
pathways.
Antioxidant and Pro-Oxidant Activities
Oxidative stress is a major contributor to cancer development
and progression [70]. It occurs when there is an imbalance between
the production of ROS and reactive nitrogen species (RNS) and the
levels or activity of antioxidant defenses. Failure to maintain this
equilibrium can lead to the destruction of important biomolecules
and ultimately to cellular damage. Despite its critical significance in
signaling mechanisms, reactive species can induce DNA lesions,
which in turn may produce mutations, known to be on the basis of
cancer onset [16, 70]. Besides, ROS/RNS can react with cellular
proteins and lipids, yielding products with carcinogenic and
mutagenic properties [70-73]. These events can promote significant
alterations to cells’ signaling, regulation and gene expression [71, 73].
It w as show ed that the urine of patients with either bladder or
prostate cancer exhibited high levels of the oxidative stress marker
8-hydroxydeoxyguanosine. This molecule is produced when ROS
cause the hydroxylation of DNA’s guanine and is excreted in urine
upon DNA repair, therefore being known as an indicator of DNA
repair and cellular oxidative stress [74]. Thus, that study illustrates
that the DNA damage induced by oxidative stress may be an
important pathological feature of bladder cancer patients.
The structure of tea catechins has a major influence in their
antioxidant properties [28, 31, 75]. However, these compounds are
relatively unstable, and it is common for catechins to suffer
oxidation processes. This oxidation can either be performed by
catechins themselves (known as auto oxidation), or can be
catalyzed by transition metals such as copper and iron [75]. Studies
reported that antioxidant properties of tea catechins were only
observed in vivo when animals were under oxidative stress,
contrary to in vitro studies, where these activities could nearly
always be observed. Catechins were also suggested to influence the
levels of endogenous antioxidants. A study performed on Wistar
rats showed that continuous administration of EGCG (2 mg per kg
of body weight) for 30 days was able to significantly improve
animals’ antioxidant defenses, ameliorating the oxidative stress
levels in their brains, induced by age [76]. EGCG successfully
induced a rising in the activity levels of the following antioxidant
enzymes: superoxide dismutase, catalase, glutathione peroxidase,
glutathione reductase and glucose-6-phosphate dehydrogenase, as
well as in the levels of nonenzymatic antioxidants such as L-ascorbic
acid, α -tocopherol and glutathione. Also, lipid peroxidation and
levels of protein carbonyls (markers of protein damage induced by
ROS) showed significant decrease after EGCG treatment. Moreover,
treatment with EGCG, in young Wistar rats whose brain tissue did
not displayed oxidative stress levels induced by age, did not yield
the same significant alterations in the antioxidant levels [76].
The beneficial properties of tea catechins can be extended to
many different types of cancer, since the carcinogenic events and
properties of tumor cells are fairly similar in many of them. For
example, catechins and other tea polyphenols were reported to
Fig. (4). Schematic illustration of the main effects of tea components in a bladder cancer cell. Tea’s phytocomponents can exert antioxidant or pro-oxidant
activities, depending on its concentrations. When in high doses, they can induce excessive reactive oxygen species (ROS) production by mitochondria,
contributing to oxidative stress increase. On the other hand, when in moderate doses, they contribute to low production of ROS, which will p rovoke a response
in the cell, augmenting the endogenous antioxidant defenses. These compounds can also interfere in multiple cell signaling pathways, promoting cell cycle
arrest, inducing cell apoptosis and decreasing cells ability to migrate.

Tea and Bladder Cancer Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 31
protect against skin [10, 44, 54], renal [2], hepatic [3] and lung [8,
42] cancers. Still, in the context of bladder cancer, knowledge and
proof of all these activities by tea catechins are still lacking. In vitro
studies in normal/cancerous bladder cell lines exposed to hydrogen
peroxide (H2O2), an oxidative agent, analyzed the antioxidant
effects of the treatment with GT extract (14% polyphenols),
polyphenon-60 (PP-60, 60% pure catechins), ECG and EGCG and
concluded that ECG, EGCG and PP-60 were able to improve cell
survival. The protection afforded against apoptosis induced by
H2O2 was higher for normal bladder cells than in cancerous ones.
H2O2 exerted its apoptotic effects in normal bladder cells mainly by
inducing ROS generation. These effects were either partially
mediated by the superoxide anion or by direct H2O2 signaling.
Although the exact mechanisms by which PP-60 and the selected
catechins were able to diminish the damaging effects of H2O2 were
not thoroughly explained, it was hypothesized that these compounds
can modulate cellular gene expression, possibly by causing the
induction of protein kinase C and downregulation of nuclear factor
kappa beta. These alterations in cell signaling would suppress cell
death mechanisms and counterbalance ROS production [46].
Of note, tea catechins also possess the ability to generate ROS .
The mechanisms of hydrogen atoms/electron transfer and oxidation
processes catalyzed by transition metals often originate highly
reactive species, such as quinone, semi-quinone radicals and other
free radicals (for review see [75]). For instance, the incubation of
several carcinoma cell lines with EGCG resulted in inhibition of
phosphorylation and reduced protein levels of epidermal growth
factor receptor (EGFR) and HER-2/neu, both members of the ERBB
receptor family [77]. These effects were delayed with addition of
the enzyme superoxide dismutase, suggesting that they may be, at
least partially, a result of the action of EGCG oxidation products
[77]. Therefore, these compounds can exhibit either antioxidant or
pro-oxidant properties, which are based on complex chemical
interactions (for review see [31, 75]). This fact is an important
feature to consider not only when fighting a pathological state, but
also due to toxicity that is observed when high doses of tea polyphenols
are administered. For instance, moderate doses of polyphenols
induce low ROS production and activate the nuclear factor Nrf2,
which can then translocate to the cell nucleu s and stimulate th e
expression of antioxidant enzymes [78]. On the other hand, excessive
amounts of polyphenols will produce higher levels of ROS.
Treatment of CF-1 mice with a single oral dose of 1500 mg/kg
EGCG reduced the animals’ survival by 85% and the administration
of daily doses of 500 and 750 mg/kg decreased survival by 20%
and 75%, respectively. High doses of orally administered EGCG
may induce hepatocyte toxicity and even mortality in mice, in a
dose and time-dependent manner. These events were suggested to be
caused by EGCG induction of oxidative stress [79].
Tea catechins may have nefarious effects on normal cells, or
even activ ate certain tumor survival pathways. For example, the
catechins ECG and EGCG were capable of activating hypoxia-
inducible factor 1 in a human breast cancer cell line, responsible for
aiding tumor development and survival under hypoxic conditions.
This was due to their ability to chelate iron ion s, given that
activation was blocked when this metal was added [80]. More
recently, a study reported that EGCG, when used to treat human
lung and skin cell lines, was responsible for an increase in DNA
damage, genetic mutation frequency and apoptosis. These effects
were attributed to EGCG’s reductive ability. It was suggested that
this catechin may hav e more detrimental action in healthy cells than
those of oxidative species, such as H2O2, and known highly toxic
chemotherapeutic agents, such as cisplatin [81].
Cell Signaling Alterations and Other Reported Mechanisms
The numerous and complex signaling pathways that exist in a
cell are extremely important to maintain its homeodynamics and
normal functioning. The disclosure of these pathways has become
very important in the study of several diseases. Cancer cells
normally display several differences in metabolism [82], gene
expression and survival mechanisms, among others. Thus, as
expected, tea and its components can inhibit carcinogenesis through
a wide variety of mechanisms (for review see [68, 83]). These
compounds may induce apoptosis, deregulate cell cycle, inhibit
growth, proliferation, angiogenesis, enzyme activities and gene
transcription, among many other mechanisms (for review see [83]).
These ev ents are controlled by a series of different pathw ays that
may interact amongst themselves, making this subject very complex
and requiring a thorough analysis, which is not yet completely
disclosed [83].
Concerning bladder cancer, some studies were performed
in vivo and in vitro (Table 2), elucidating possible mechanisms by
which tea and its individual components exert their chemopreventive
effects [83, 84]. In vitro studies were performed in many different
bladder cancer cell lines, and reported the anticarcinogenic effects
of tea components (mainly EGCG). The effects of treatment with
increasing concentrations of EGCG in rat bladder TCC cells and
in mouse leukemia cells are well studied. DNA ladder assays
confirmed that cell survival decreased in an EGCG time and dose-
dependent manner in both cell lines. Moreover, histological
observations revealed cellular shrinkage, pyknosis and cell surface
blebbing, also verified in another study [43, 45]. Contrary to
leukemia cells, the bladder cancer cell line showed weak banding
pattern on the DNA ladder assay. Still, cell survival decrease was
confirmed, illustrating that the anticarcinogenic effects of EGCG in
these cells may not include apoptosis induction as a primary
mechanism of action [45]. Analysis of DNA fragmentation was also
performed on NBT-II bladder tumor cells treated with different
concentrations of EGCG. The cells displayed growth inhibition and
evidence of cell cy cle arrest in the G0/G1 phase. Further analysis
revealed that EGCG treatment induced a significant downregulation
of CCND1 gene expression (which encodes the cyclin D1 protein),
decreased expression of cyclin D1, cdk4 and cdk6 proteins and also
decreased hyperphosphorylation of pRb, illustrating that EGCG
may interfere in cyclin D1-cdk4/6-Rb protein machinery, causing
cells’ cycle arrest [55]. Similar results were reported using other
bladder cancer cell lines, which showed a significant growth
inhibition and decrease in cell migration/invasion assays, induced
by EGCG [38, 43]. EGCG activated the p42/44 MAP kinase
pathway and consequently its signaling target STAT3, which is
implicated in several models of malignant tumor progression.
However, in other studies, inhibition of these pathways did not alter
the reduction in cellular migration induced by EGCG, suggesting
that these may not be the sole mechanisms through which EGCG
exhibits its antimetastatic effects [38]. Further studies revealed that
EGCG inactivated the Akt kin ase pathway, also implicated in
cellular migration, and that this mechanism may be underlying the
observed antimetastatic activity of EGCG [38, 43]. Indeed,
antimetastatic properties of EGCG could also be observed in other
studies, and may be related with interference in cellular adhesion
mechanisms since it was demonstrated a reduced expression of N-
cadherin, β -, and ɣ -catenin proteins in cells treated with EGCG
[38]. Besides Akt inactivation, others also correlated the apoptotic
effects of EGCG treatment on bladder cancer cells with the reported
decrease in heat-shock protein 27 and Bcl-2 protein (involved in the
inhibition of cell apoptosis), and the increase in Bad and Bax levels,
known proapoptotic proteins [43]. These events may also be
responsible for increased activity of caspases 3 and 9 in bladder
cancer cells treated with EGCG, furth er illustrating that EGCG
activates the apoptotic mitochondrial pathway [43].
The suggestion that EGCG is capable of inducing cell apoptosis
was also supported by other studies, performed in murine bladder
cancer cells treated with EGCG combined with gold nanoparticles

32 Anti-Cancer Ag ents in Medicinal Chemistry, 2015, Vol. 15, No. 1 Conde et al.
that show ed that this combined treatment successfully reduced
tumor cell viability, increased the number of apoptotic bodies
formed, decreased the levels of antiapoptotic Bcl-XL, increased the
levels of proapoptotic proteins such Bad and Bax and increased the
expression levels of caspases 3 and 7. Altogether, these findings
also suggest an involvement of mitochondrial apoptotic pathway in
the EGCG mechanism of action [56].
As discussed, the majority of in vitro studies report different
effects of tea (and particularly EGCG), ranging from induction of
apoptosis, cell cycle arrest and inhibition of cell proliferation,
among others. Also, alterations in many different proteins and
mechanisms were verified after cancer cells treatment. Despite
interfering in seemingly different and unrelated pathways, certain
effects of EGCG may explain many of its different anticancer
activities. In molecular mod eling studies, the main intracellular
targets of tea and its components reported so far include membrane
tyrosine kinase receptors such as HER-2/neu and EGFR, which
EGCG can inactivate by direct binding to the active tyrosine kinase
sites, modifying protein conformation or altering the lipid rafts [77,
85-87]. Avoiding receptor activation modifies cell signaling
pathways and consequently alter gene transcription and protein
activity. Interference in those receptors may inactivate the
downstream signaling proteins such as Akt and ERK1/2 [87], thus
modulating their related pathways. This results in the altered
expression of p53 and p27 proteins, along with other known cell
cycle regulators and may cause cell cycle arrest [87]. Another result
of the interference in the Akt activation is the dephosphorylation of
forkhead transcription factors FOXO and the proapoptotic Bad
protein, among other downstream signaling proteins [88]. This may
cause suppression of angiogenesis [89], enhance the expression
of proapoptotic proteins and inactivate antiapoptotic proteins
such as Bcl-XL, thus activating cell apoptosis [87]. Therefore, we
hypothesize that interference in Akt activation is a tremendously
important property of EGCG and may be the base of its anticancer
abilities, reflected in many different cell mechanisms, due to the
several pathways in which Akt participates.
Nowadays researchers are already able to chemically synthesize
catechin analogs, through series of complex chemical reactions [90,
91], in order to stabilize their structure and enhance their properties.
Studies reported that protecting the hydroxyl groups in the rings
using acetate groups stabilizes the catechins structure and yields
effective prodrugs [92, 93]. Also, chemical enhancement of radical
scavenging ability of catechin analogs has been achieved by
altering the bonds between the B and C rings and the overall
geometry of the catechins structure [94]. However, to our
knowledge, such compounds have not yet been tested in bladder
cancer cell lines. Neverth eless, their anticancer properties were
reported in several cancer types. For example, treatmen t of
leukemia, breast and prostate cancer cells with EGCG analogs
showed that these compounds were more effective at inducing
apoptosis in cells than natural EGCG [93]. Concurrently, others
treated melanoma, breast, lung and colorectal cancer cells with
natural purified EGCG and ECG analogs [95]. Similarly to previous
studies, synthetic catechins displayed higher apoptotic and
antiproliferative properties. Also, smaller quantities of the analogs
were needed to achieve these results, compared to ones used for
EGCG treatments [95].
Importantly, although polyphenols are the major chemical
components of tea, its beneficial effects may also be exerted by
other constituents. Although only caffeine is present in tea, both
caffeine and pentoxifylline showed positive synergistic effects on
treatment of bladder cancer cells with the alkylator drug Thiotepa,
which is commonly used for treating bladder cancer [96]. After
treatmen t with these methylxanthines, survival of the cells
previously treated with Thiotepa decreased significantly. Further
analysis revealed that these m ethylxanthines may prevent G2 cell
cycle delay, which is a normal defense mechanism that allows the
cells to repair their DNA after Thiotepa aggression. In this way,
lethal chromosomal aberrations increased and cell death was
provoked [96].
GT extract, alone [97] and combined with a mixture of lysine,
proline, arginine, L-ascorbic acid and N-acetyl cysteine [48] also
showed positive effects in vitro. Treatment of bladder tumor cells
with different concentrations of GT extract (comprised of 43.0%
EGCG and 13.7% ECG, among smaller quantities of other catechins)
resulted in induction of cellular actin polymerization, a protein that
forms the cells’ microfilaments and is typically depolymerized in
cancer cells, thus enhancing cell adhesion and inhibiting motility.
This mechanism may be due to a GT induced increase in Rho
activity, a regulator of actin stress fiber formation [97]. In another
study, GT extract (containing 80% polyphenols, 30% catechins and
1% caffeine, among other components) also showed antimetastatic
effects. Analysis of cell proliferation, protein expression and
invasive potential in bladder cancer cells treated with different
concentrations of the mixture revealed significant inhibition of
cell invasion and a dose-dependent decrease in secretion of
metalloproteinases 2 and 9, which are enzymes typically secreted
by highly metastatic cancer cells th at allow them to d estroy
components of the extracellular matrix and migrate to other
locations in the tissues [48].
In vivo studies of tea effects on bladder tumors were performed
on mice [38, 43, 56, 57] and rats [45, 58, 67] (see Table 2).
Fortunately, some of the effects of tea components observed in vitro
have been, to some extent, also reported in vivo. EGCG was added
to drinking water (0.05% w/v) and consumed by 6 week old
BALB/c nude mice, 7 days before subcutaneous injection of
bladder cancer cells and 15 days after the referred injection. Results
showed significant decrease in tumor volume. Also, no side effects
were observed, aside from a slight weight gain in the treated mice
[38]. In another study using female C3H/He mice with BBN-
induced bladder cancer, which were fed with a solution of GT
polyphenols (in a concentration of 0.5%), histological and immuno-
histochemical analysis of urinary bladder tissues revealed that a 24
week treatment with GT polyphenols reduced tumor growth and
microvessel density. These results illustrate that these compounds
also possess antiangiogenic effects, which may be responsible for
the reduction in tumor growth, although no specific mechanistic
studies were performed [57].
A more recent study also demonstrated inhibition of tumor
growth in BALB/c nude mice fed with EGCG (in concentrations of
25 and 50 mg/kg per day) during a 42 days period after cancer
induction. The mechanism of action proposed includes activation of
intrinsic mitochondrial apoptotic pathway and is based on in vitro
studies, discussed above [43]. Significant reduction of tumor
growth was also reported in bladder tumor-induced male mice
treated with EGCG conjugated with gold nanoparticles. This result
was accompanied by a decrease in cellular vascular endothelial
growth factor expression, a protein known for stimulating vasculo-
genesis and angiogenesis. These findings suggest that, besides the
apoptotic effects demonstrated by the conjugated treatment in vitro,
the combination of EGCG plus nanoparticles may also be responsible
for an angiogenesis inhibition in vivo, most likely through suppression
of vascular endothelial growth factor. Nevertheless, the exact
mechanisms are still unclear [56]. In a study using male Wistar rats
with BBN-induced bladder cancer, animals treated with GT extract
and powdered GT leaves displayed significant decrease in tumor
volume. Moreover, histological observations revealed an improvement
of histological grade of the induced bladder tumors and tendency to
decreased depth of invasion [67]. Ingestion of GT powdered leaves
(2.5% mixed into a feeding pellet) before and after cancer induction
in male Wistar rats resulted in a significant decrease in the number
of tumors per rat and in mean volume per tumor, relatively to

Tea and Bladder Cancer Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 33
controls, as well as improvement of histological grade of the tumors
[58]. Treatment of Fisher 344 rats with a solution of 200 µM EGCG
also induced a significant decrease in tumor growth [45]. The
authors suggested that, while EGCG itself is effective as antitumor
agent, its isolation and administration to patients would be difficult,
mainly due to economic issues. Hence, the administration of GT
leaves seems to be a better solution to counteract bladder cancer,
providing an excellent quantity of other beneficial compounds such
as other catechins, caffeine, quercetin and vitamins [58, 67].
Concerning in vivo and in vitro research studies, many
promising results have been obtained (see Table 2). Indeed, tea
extracts and components, either natural or synthetic, showed great
anticancer activities. For example, studies performed on cancer cell
lines demonstrated the efficacy of GT extracts, catechins extracted
from tea and synthetic catechin analogs. However, th ese studies
present some cons that may hamper the extrapolation of the
conclusions to human health applications, such as the fact that the
concentrations of catechins (and other bioactive compounds) tested
in vitro are normally much higher than those verified in vivo.
Moreover, differences between animal species subjected to research
and humans may also hamper the correct interpretation, extrapolation
and practical application of the results and conclusions.
CONCLUDING REMARKS
Tea is one the most consumed beverages in the world. Its
beneficial health effects, for so long advertised by traditional
medicine, are now being more deeply investigated by modern
science. Several studies attributed to tea the ability to protect
against infections, chronic diseases and cancer. Tea catechins, the
main phenolic compounds and the most active, are thought to be
responsible by tea’s antioxidant and chemopreventive abilities,
which include induction of apoptosis in cancer cells, inhibition of
metastization and angiogenesis, cell cycle arrest and enhancement
of antioxidant defenses. Bladder cancer is thought to be preventable
by modification of dietary factors, and tea consumption has been
proposed as a possible defense against this cancer type. However,
the fact that tea consumption is indeed an asset in bladder cancer
chemopreventive and chemo therapeutic fields still raises some
controversy. The molecular mechanisms by which tea and/or its
phytochemicals exert the possible protective effects remain unclear.
A key feature of cancer cells is proliferation, which has been
associated with changes in cellular metabolism. Although some
studies showed the potential effect of tea and its components to
change cancer cells metabolism, it remains to be tested in bladder
cancer cells. Moreov er, cell cycle alterations induced by tea
consumption and tea phytochemicals in bladder cancer cells should
also be explored. Nevertheless, tea’s health benefits seem undeniable,
and its ability to inhibit tumor spreading and metastasis was verified
in in vitro and in vivo carcinogenic models. The complex mechanisms
by which tea and its components may exert their benefits are still
poorly understood, and a general consensus has not been achieved
yet. Further studies are needed, since studying tea’s compounds and
mechanisms of action may yield new insights in developing new
therapeutic strategies fo r the treatment of bladder cancer.
CONFLICT OF INTEREST
The author(s) confirm th at this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
M.G. Alves (SFRH/BPD/80451/2011) was financed by FCT.
P.F. Oliveira was financed by FCT through FSE and POPH funds
(Programa Ciência 2008). The authors also acknowledge the
Programa COMPETE (PEst-C/SAU/UI0709/2014).
Table 2. Summary of the main effects observed in several in vivo and in vitro studies focused on the effects of tea and its phytochemicals in
bladder cancer.
Effects Observed
Tea/ Compound
Tested
Tumor size
Metastiz ation
Angiogenesis
Apoptosis
Cell cycle arrest
Morphological
changes
Cell cytotoxicity
Chromosome
damage
EGCG [38, 43, 56]     nd nd nd nd
Mouse Mode l
GT polyphenols [57]   nd nd nd nd nd nd
EGCG [45]  nd nd nd nd nd nd nd
Powdered GT leaves [58, 67]   nd nd nd nd nd nd
GT [67]   nd nd nd nd nd nd
OT [67]   nd nd nd nd nd nd
In vivo Studies
Rat Model
BT [67]  nd nd nd nd nd nd nd
NBT-II [55], J82 [38], UM-UC-3 [38], EJ
[38], KK47 [38], T24 [38], TCCSUP [38],
TSGH-8301 [43], AY-27 [45], L1210 [45]
EGCG   nd    nd nd
T24, TCCSUP, SW780 TCC, RT4, Urotsa
[46] PP-60+EGCG +ECG (after insult with H2O2) nd nd nd  nd nd nd nd
Lysine+proline +arg inine+ ascorbic acid+ GT
extract [48] nd  nd nd nd nd nd nd
T24 [48, 96]
Caffeine/ pentox ifylline+ Thiotepa [90] nd nd nd nd  nd  
In vitro Studies
(bladder cancer cell lines)
HUC-PC, MC-T11 [97] GT extract nd  nd nd nd nd nd nd
Legend: BT - black tea; ECG – epicatechin-3-gallate; EGCG - epigallocatechin 3-gallate; GT - green tea; OT - oolong tea; PP-60 - polypheno n-60;  - Reduced/inhibited;  -
Increased; nd - not determined. Superscript numbers are references as indicated in references section.

34 Anti-Cancer Ag ents in Medicinal Chemistry, 2015, Vol. 15, No. 1 Conde et al.
LIST OF ABBREVIATIONS
BT = Black tea
BBN = N-butyl-N- (4-hydroxybutyl) nitrosamine
EC = Epicatechin
ECG = Epicatechin-3-gallate
EGC = Epigallocatechin
EGCG = Epigallocatechin-3-gallate
EGFR = Epidermal growth facto r receptor
GT = Green tea
H2O2 =
Hydrogen peroxide
OT = Oolong tea
PO = Polyphenol oxidase
PP-60 = Polyphenon-60
RNS = Reactive nitrogen species
ROS = Reactive oxygen species
pRb = Retinoblastoma protein
TCC = Transitional cell carcinoma
WT = White tea
REFERENCES
[1] Almajano, M.P.; Vila, I.; Gines, S. Neuroprotective effects of white
tea against oxidative stress-induced toxicity in striatal cells.
Neurotox. Res., 2011, 20(4), 372-378.
[2] Carvalho, M.; Jerónimo, C.; Valentão, P.; Andrade, P.B.; Silva,
B.M. Green tea: A promising anticancer agent for renal cell
carcinoma. Food Chem., 2010, 122(1), 49-54.
[3] Darvesh, A.; Bishayee, A. Chemopreventive and therapeutic
potential of tea polyphenols in hepatocellular cancer. Nutr. Cancer,
2013, 65(3), 329–344.
[4] Dias, T.R.; Tomás, G.; Teixeira, N.F.; Alves, M.G.; Oliveira, P.F.;
Silva, B.M. Wh ite tea (Camellia Sinensis (L.)): Antioxidant
properties and beneficial health effects. Int. J. Food Sci. Nutr. Diet,
2013, 2, 1-15.
[5] Huang, M.T.; Xie, J.G.; Wang, Z.Y.; Ho, C.T.; Lou, Y.R.; Wang,
C.X.; Hard, G.C.; Conney, A.H. Effects of tea, decaffeinated tea,
and caffeine on UVB light-induced complete carcinogenesis in
SKH-1 mice: Demonstration of caffeine as a biologically important
constituent of tea. Cancer Res., 1997, 57(13), 2623-2629.
[6] Khan, N.; Mukhtar, H. Tea polyphenols for health promotion. Life
Sci., 2007, 81(7), 519-533.
[7] Kumar, M.; Sharma, V.L.; Sehgal, A.; Jain, M. Protective effects of
green and white tea against benzo(a)pyrene induced oxidative
stress and DNA damage in murine model. Nutr. Cancer, 2012,
64(2), 300-306.
[8] Mao, J.T.; Nie, W.X.; Tsu, I.H.; Jin, Y.S.; Rao, J.Y.; Lu, Q.Y.;
Zhang, Z.F.; Go, V.L.; Serio, K.J. White tea extract induces
apoptosis in non-small cell lung cancer cells: The role of
peroxisome proliferator-activated receptor-{gamma} and 15-
lipoxygenases. Cancer Prev. Res. (Phila.), 2010, 3(9), 1132-1140.
[9] Moderno, P.M.; Carvalho, M.; Silva, B.M. Recent patents on
Camellia sinensis: Source of health promoting compounds. Rec.
Pat. Food Nutr. Agric., 2009, 1(3), 182-192.
[10] Wang, Z.Y.; Huang, M.T.; Ho, C.T.; Chang, R.; Ma, W.; Ferraro,
T.; Reuhl, K.R.; Yang, C.S.; Conney, A.H. Inhibitory effect of
green tea on the growth of established skin papillomas in mice.
Cancer Res., 1992, 52(23), 6657-6665.
[11] Barot, K.P.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Novel anticancer
agents and targets: Recent advances and future perspectives. Mini
Rev. Med. Chem., 2013, 13(9), 1239-1255.
[12] Coseri, S. Natural products and their analogues as efficient
anticancer drugs. Mini Rev. Med. Chem., 2009, 9(5), 560-571.
[13] Carvalho, M.; Ferreira, P.J.; Mendes, V.S.; Silva, R.; Pereira, J.A.;
Jeronimo, C.; Silva, B.M. Human cancer cell antiproliferative and
antioxidant activities of Juglans regia L. Food Chem. Toxicol.,
2010, 48(1), 441-447.
[14] Carvalho, M.; Silva, B.M.; Silva, R.; Valen tao, P.; Andrade, P.B.;
Bastos, M.L. First report on Cydonia oblonga Miller anticancer
potential: Differential antip roliferative effect against human kidney
and colon cancer cells. J. Agric. Food Chem., 2010, 58(6), 3366-
3370.
[15] Pelucchi, C.; Bosetti, C.; Negri, E.; Malvezzi, M.; La Vecchia, C.
Mechanisms of disease: The epidemiology of bladder cancer. Nat.
Clin. Pract. Urol., 2006, 3(6), 327-340.
[16] Crawford, J. The origins of bladder cancer. Lab. Invest., 2008,
88(7), 686–693.
[17] Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D.
Global cancer statistics. CA-Cancer J. Clin., 2011, 61(2), 69-90.
[18] Kobeissi, L.H.; Yassine, I.A.; Jabbour, M.E.; Moussa, M.A.;
Dhaini, H.R. Urinary bladder cancer risk factors: A lebanese case-
control study. Asian Pac. J. Cancer Prev., 2013, 14(5), 3205-3211.
[19] Kurahashi, N.; Inoue, M.; Iwasaki, M.; Sasazuki, S.; Tsugane, S.
Coffee, green tea, and caffeine consumption and subsequent risk of
bladder cancer in relation to smoking status: A prospective study in
Japan. Cancer Sci., 2009, 100(2), 294-291.
[20] Wang, J.; Wu, X.; Kamat, A.; Barton Grossman, H.; Dinney, C.P.;
Lin, J. Fluid intake, genetic variants of UDP-glucuronosyl-
transferases, and bladder cancer risk. Br. J. Cancer, 2013, 108(11),
2372-2380.
[21] Hemelt, M.; Hu, Z.; Zhong, Z.; Xie, L.P.; Wong, Y.C.; Tam, P.C.;
Cheng, K.K.; Ye, Z.; Bi, X.; Lu, Q.; Mao, Y.; Zhong, W.D.;
Zeegers, M.P. Fluid intake and the risk of bladder cancer: Results
from the South and East China case-control study on bladder
cancer. Int. J. Cancer, 2010, 127(3), 638-645.
[22] Nagano, J.; Kono, S.; Preston, D.L.; Moriwaki, H.; Sharp, G.B.;
Koyama, K.; Mabuchi, K. Bladder-cancer incidence in relation to
vegetable and fruit consumption: A prospective study of atomic-
bomb survivors. Int. J. Cancer, 2000, 86(1), 132-138.
[23] Pastore, R.L.; Fratellone, P. Potential health benefits of green tea
(Camellia sinensis): A narrative review. Explore (NY), 2006, 2(6),
531-539.
[24] Graham, H.N. Green tea composition, consumption, and
polyphenol chemistry. Prev. Med., 1992, 21(3), 334-350.
[25] Li, S.; Lo, C .Y.; Pan, M.H. ; Lai, C.S.; Ho, C.T. Black tea:
Chemical analysis and stability. Food Funct., 2013, 4(1), 10-18.
[26] Lin, Y.S.; Tsai, Y.J.; Tsay, J.S.; Lin, J.K. Factors affecting the
levels of tea polyphenols and caffeine in tea leaves. J. Agric. Food
Chem., 2003, 51(7), 1864-1873.
[27] Zaveri, N.T. Green tea and its polyphenolic catechins: Medicinal
uses in cancer and noncancer applications. Life Sci., 2006, 78(18),
2073-2080.
[28] Aboul-Enein, H.Y.; Berczynsk, P.; Kruk, I. Phenolic compounds:
The role of redox regulation in neurodegenerative disease and
cancer. Mini Rev. Med. Chem., 2013, 13(3), 385-398.
[29] Yang, Z.; Xu, Y.; Jie, G.; He, P.; Tu, Y. Study on the antioxidant
activity of tea flowers (Camellia sinensis). Asia Pac. J. Clin. Nutr.,
2007, 16(Suppl 1), 148-152.
[30] Costa, R.M.; Magalhaes, A.S.; Pereira, J.A.; Andrade, P.B.;
Valentao, P.; Carvalho, M.; Silva, B.M. Evaluation of free radical-
scavenging and antihemolytic activities of quince (Cydonia
oblonga) leaf: A comparative study with green tea (Camellia
sinensis). Food Chem. Toxicol., 2009, 47(4), 860-865.
[31] Braicu, C.; Ladomery, M.R.; Chedea, V.S.; Irimie, A.; Berindan-
Neagoe, I. The relationship between the structure and biological
actions of green tea catechins. Food Chem., 2013, 141(3), 3282-
3289.
[32] Unachukwu, U.J.; Ahmed, S.; Kavalier, A.; Lyles, J.T.; Kennelly,
E.J. White and green teas (Camellia sinensis var. sinensis):
Variation in phenolic, methylxanthine, and antioxidant profiles. J.
Food Sci., 2010, 75(6), C541-C548.
[33] Nanjo, F.; Mori, M.; Goto, K.; Hara, Y. Radical scavenging activity
of tea catechins and their related compounds. Biosci. Biotechnol.
Biochem., 1999, 63(9), 1621-1623.
[34] Gorjanovic, S.; Komes, D.; Pastor, F.T.; Belscak-Cvitanovic, A.;
Pezo, L.; Hecimovic, I.; Suznjevic, D. Antioxidant capacity of teas

Tea and Bladder Cancer Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 35
and herbal infusions: Polarographic assessment. J. Agric. Food
Chem., 2012, 60(38), 9573-9580.
[35] Cooper, R.; Morre, D.J.; Morre, D.M. Medicinal benefits of green
tea: Part II. Review of anticancer properties. J. Altern.
Complement. Med., 2005, 11(4), 639-652.
[36] Suganuma, M.; Okabe, S.; Sueoka, N.; Sueoka, E.; Matsuyama, S.;
Imai, K.; Nakachi, K.; Fujiki, H. Green tea and cancer
chemoprevention. Mutat. Res., 1999, 428(1), 339-344.
[37] Kada, T.; Kaneko, K.; Matsuzaki, S.; Matsuzaki, T.; Hara, Y.
Detection and chemical identification of natural bio-antimutagens.
A case of the green tea factor. Mutat. Res., 1985, 150(1), 127-132.
[38] Rieger-Christ, K.M.; Hanley, R.; Lodowsky, C.; Bernier, T.;
Vemulapalli, P.; Roth, M.; K im, J.; Yee, A.S.; Le, S.M.; Marie,
P.J.; Libertino, J.A.; Summerhayes, I.C. The green tea compound,
(-)-epigallocatechin-3-gallate downregulates N-cadherin and
suppresses migration of bladder carcinoma cells. J. Cell Biochem.,
2007, 102(2), 377-388.
[39] Cross, S.E.; Jin, Y.S.; Lu, Q.Y.; Rao, J.; Gimzewski, J.K. Green tea
extract selectively targets nanomechanics of live metastatic cancer
cells. Nanotechnology, 2011, 22(21), 215101.
[40] Fernandez, P.L.; Martin, M.J.; Gonzalez, A.G.; Pablos, F. HPLC
determination of catechins and caffeine in tea. Differentiation of
green, black and instant teas. Analyst, 2000, 125(3), 421-425.
[41] Hayatsu, H.; Inada, N.; Kakutani, T.; Arimoto, S.; Negishi, T.;
Mori, K.; Okuda, T.; Sakata, I. Suppression of genotoxicity of
carcinogens by (-)-epigallocatechin gallate. Prev. Med., 1992,
21(3), 370-376.
[42] Yamauchi, R.; Sasaki, K.; Yoshida, K. Identification of
epigallocatechin-3-gallate in green tea polyphenols as a potent
inducer of p53-dependent apoptosis in the human lung cancer cell
line A549. Toxicol. in vitro, 2009, 23(5), 834-839.
[43] Chen, N.G.; Lu, C.C.; Lin, Y.H.; Shen, W.C.; Lai, C.H.; Ho, Y.J.;
Chung, J.G.; Lin, T.H.; Lin, Y.C.; Yang, J.S. Proteomic approaches
to study epigallocatechin gallate-provoked apoptosis of TSGH-
8301 human urinary bladder carcinoma cells: Roles of AKT and
heat shock protein 27-modulated intrinsic apoptotic pathways.
Oncol. Rep., 2011, 26(4), 939-947.
[44] Fujiki, H.; Yoshizawa, S.; Horiuchi, T.; Suganuma, M.; Yatsunami,
J.; Nishiwaki, S.; Okabe, S.; Nishiwaki-Matsushima, R.; Okuda, T.;
Sugimura, T. Anticarcinogenic effects of (-)-epigallocatechin
gallate. Prev. Med., 1992, 21(4), 503-509.
[45] Kemberling, J.K.; Hampton, J.A.; Keck, R.W.; Gomez, M.A.;
Selman, S.H. Inhibition of bladder tumor growth by the green tea
derivative epigallocatechin-3-gallate. J. Urol., 2003, 170(3), 773-776.
[46] Coyle, C.H.; Philips, B.J.; Morrisroe, S.N .; Chancellor, M.B.;
Yoshimura, N. Antioxidant effects of green tea and its polyphenols
on bladder cells. Life Sci., 2008, 83(1), 12-18.
[47] Qin, J.; Wang, Y.; Bai, Y.; Yang, K.; Mao, Q.; Lin, Y.; Kong, D.;
Zheng, X.; Xie, L. Epigallocatechin-3-gallate inhibits bladder
cancer cell invasion via suppression of NF-kappaB-mediated
matrix metalloproteinase-9 expression. Mol. Med. Rep ., 2012, 6(5),
1040-1044.
[48] Roomi, M.W.; Ivanov, V.; Kalinovsky, T.; Niedzwiecki, A.; Rath,
M. Antitumor effect of ascorbic acid, lysine, proline, arginine, and
green tea extract on bladder cancer cell line T-24. Int. J. Urol.,
2006, 13(4), 415-419.
[49] Hashimoto, T.; He, Z.; Ma, W.Y.; Schmid, P.C.; Bode, A.M.;
Yang, C.S.; Dong, Z. Caffeine inhibits cell proliferation by G0/G1
phase arrest in JB6 cells. Cancer Res., 2004, 64(9), 3344-3349.
[50] Nawrot, P.; Jordan, S.; Eastwood, J.; Rotstein, J.; Hugenholtz, A.;
Feeley, M. Effects of caffeine on human health. Food Addit.
Contam., 2003, 20(1), 1-30.
[51] Dias, T.R.; Alves, M.G.; Tomás, G.D.; Socorro, S.; Silva, B.M.;
Oliveira, P.F. White tea as a promising antioxidant medium
additive for sperm storage at room temperature: A comparative
study with green tea. J. Agric. Food Chem., 2014, 62(3), 608-617.
[52] Lee, L.S.; Lee, N.; Kim, Y.H.; Lee, C.H.; Hong, S.P.; Jeon, Y.W.;
Kim, Y.E. Optimization of ultrasonic extraction of phenolic
antioxidants from green tea using response surface methodology.
Molecules, 2013, 18(11), 13530-13545.
[53] Mandel, H.G. Update on caffeine consumption, disposition and
action. Food Chem. Toxicol., 2002, 40(9), 1231-1234.
[54] Lu, Y.P.; Lou, Y.R.; Xie, J.G.; Peng, Q.Y.; Liao, J.; Yang, C.S.;
Huang, M.T.; Conney, A.H. Topical applications of caffeine or (-)-
epigallocatechin gallate (EGCG) inhibit carcinogenesis and
selectively increase apoptosis in UVB-induced skin tumors in mice.
Proc. Natl. Acad. Sci. U.S.A., 2002, 99(19), 12455-12460.
[55] Chen, J.J.; Ye, Z.Q.; Koo, M.W. Growth inhibition and cell cycle
arrest effects of epigallocatechin gallate in the NBT-II bladder
tumour cell line. BJU Int., 2004, 93(7), 1082-1086.
[56] Hsieh, D.S.; Wang, H.; Tan, S.W.; Huang, Y.H.; Tsai, C.Y.; Yeh,
M.K.; Wu, C.J. The treatment of bladder cancer in a mouse model
by epigallocatechin-3-gallate-gold nanoparticles. Biomaterials,
2011, 32(30), 7633-7640.
[57] Sagara, Y.; Miyata, Y.; Nomata, K.; Hayashi, T.; Kanetake, H.
Green tea polyphenol suppresses tumor invasion and angiogenesis
in N-butyl-(-4-hydroxybutyl) nitrosamine-induced bladder cancer.
Cancer Epidemiol., 2010, 34(3), 350-354.
[58] Sato, D.; Matsushima, M. Preventive effects of urinary bladder
tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rat
by green tea leaves. Int. J. Urol., 2003, 10(3), 160-166.
[59] Bianchi, G.D.; Cerhan, J.R.; Parker, A.S.; Putnam, S.D.; See,
W.A.; Lynch, C.F.; Cantor, K.P. Tea consumption and risk of
bladder and kidney cancers in a population-based case-control
study. Am. J. Epidemiol., 2000, 151(4), 377-383.
[60] Zheng, W.; Doyle, T.J.; Kushi, L.H.; Sellers, T.A.; Hong, C.P.;
Folsom, A.R. Tea consumption and cancer incidence in a
prospective cohort study of postmenopausal women. Am. J.
Epidemiol., 1996, 144(2), 175-182.
[61] Bruemmer, B.; White, E.; Vaughan, T.L.; Cheney, C.L. Fluid
intake and the incidence of bladder cancer among middle-aged men
and women in a three-county area of western Washington. Nutr.
Cancer, 1997, 29(2), 163-168.
[62] Claude, J.; Kunze, E.; Frentzel-Beyme, R.; Paczkowski, K.;
Schneider, J.; Schubert, H. Life-style and occupational risk factors
in cancer of the lower urinary tract. Am. J. Epidemiol., 1986,
124(4), 578-589.
[63] Demirel, F.; Cakan, M.; Yalcinkaya, F.; Topcuoglu, M.; Altug, U.
The association between personal habits and bladder cancer in
Turkey. Int. Urol. Nephrol., 2008, 40(3), 643-647.
[64] Lu, C.M.; Lan, S.J.; Lee, Y.H.; Huang, J.K.; Huang, C.H.; Hsieh,
C.C. Tea consumption: Fluid intake and bladder cancer risk in
Southern Taiwan. Urology, 1999, 54(5), 823-828.
[65] Morgan, R.W.; Jain, M.G. Bladder cancer: Smoking, beverages and
artificial sweeteners. Can. Med. Assoc. J., 1974, 111(10), 1067-
1070.
[66] Heilbrun, L.K.; Nomura, A.; Stemmermann, G.N. Black tea
consumption and cancer risk: A prospective study. Br. J. Cancer,
1986, 54(4), 677-683.
[67] Sato, D. Inhibition of urinary bladder tumors induced by N-butyl-
N-(4-hydroxybutyl)-nitrosamine in rats by green tea. Int. J. Urol.,
1999, 6(2), 93-99.
[68] Yang, C.S.; Wang, H. Mechanistic issues concerning cancer
prevention by tea catechins. Mol. Nutr. Food Res., 2011, 55(6),
819-831.
[69] Lambert, J.D.; Yang, C.S. Cancer chemopreventive activity and
bioavailability of tea and tea polyphenols. Mutat. Res., 2003, 523,
201-208.
[70] Ziech, D.; Franco , R.; Georgakilas, A.G.; Georgakila, S.;
Malamou-Mitsi, V.; Schoneveld, O.; Pappa, A.; Panayiotidis, M.I.
The role of reactive oxygen species and oxidative stress in
environmental carcinogenesis and biomarker development. Chem.
Biol. Interact., 2010, 188(2), 334-339.
[71] Valko, M.; Rhodes, C.J.; Moncol, J.; Izakovic, M.; Mazur, M. Free
radicals, metals and antioxidants in oxidative stress-induced cancer.
Chem. Biol. Interact., 2006, 160(1), 1-40.
[72] Valavanidis, A.; Vlachogianni, T.; Fiotakis, C. 8-hydroxy-2' -
deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress
and carcinogenesis. J. Environ. Sci. Health C. Environ. Carcinog.
Ecotoxicol. Rev., 2009, 27(2), 120-139.
[73] Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B.
Oxidative stress, inflammation, and cancer: How are they linked?
Free Radic. Biol. Med., 2010, 49(11), 1603-1616.
[74] Chiou, C.C.; Chang, P.Y.; Chan, E.C.; Wu, T.L.; Tsao, K.C.; Wu,
J.T. Urinary 8-hydroxydeoxyguanosine and its analogs as DNA
marker of oxidative stress: Development of an ELISA and
measurement in both bladder and prostate cancers. Clin. Chim.
Acta, 2003, 334(1), 87-94.

36 Anti-Cancer Ag ents in Medicinal Chemistry, 2015, Vol. 15, No. 1 Conde et al.
[75] Lambert, J.D.; Elias, R.J. The antioxidant and pro-oxidant activities
of green tea polyphenols: A role in cancer prevention. Arch.
Biochem. Biophys., 2010, 501(1), 65-72.
[76] Srividhya, R.; Jyothilakshmi, V.; Arulmathi, K.; Senthilkumaran,
V.; Kalaiselvi, P. Attenuation of senescence-induced oxidative
exacerbations in aged rat brain by (-)-epigallocatechin-3-gallate.
Int. J. Dev. Neurosci., 2008, 26(2), 217-223.
[77] Hou, Z.; Sang, S.; You, H.; Lee, M.J.; Hong, J.; Chin, K.V.; Yang,
C.S. Mechanism of action of (-)-epigallocatechin-3-gallate: Auto-
oxidation -dependent inactivation of epidermal growth factor
receptor and direct effects on growth inhibition in human esophagea l
cancer KYSE 150 cells. Cancer Res., 2005, 65(17), 8049-8056.
[78] Na, H.K.; Surh, Y.J. Modulation of Nrf2-mediated antioxidant and
detoxifying enzyme induction by the green tea polyphenol EGCG.
Food Chem. Toxicol., 2008, 46(4), 1271-1278.
[79] Lambert, J.D.; Kennett, M.J.; Sang, S.; Reuhl, K.R.; Ju, J.; Yang,
C.S. Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate
in mice. Food Chem. Toxicol., 2010, 48(1), 409-416.
[80] Zhou, Y.D.; Kim, Y.P.; Li, X.C.; Baerson, S.R.; Agarwal, A.K.;
Hodges, T.W.; Ferreira, D.; Nagle, D.G. Hypoxia-inducible factor-1
activation by (-)-epicatechin gallate: potential adverse effects of
cancer chemoprevention with high-dose green tea extracts. J. Nat.
Prod., 2004, 67(12), 2063-2069.
[81] Lu, L.Y.; Ou, N.; Lu, Q.B. Antioxidant induces dna damage, cell
death and mutagenicity in human lung and skin normal cells. Sci.
Rep., 2013, 3, 3169.
[82] Vaz, C.V.; Alves, M.G.; Marques, R.; Moreira, P.I.; Oliveira, P.F.;
Maia, C.J.; Socorro, S. Androgen-responsive and nonresponsive
prostate cancer cells present a distinct glycolytic metabolism
profile. Int. J. Biochem. Cell Biol., 2012, 44(11), 2077-2084.
[83] Hou, Z.; Lambert, J.D.; Chin, K.V.; Yang, C.S. Effects of tea
polyphenols on signal transduction pathways related to cancer
chemoprevention. Mutat. Res., 2004, 555(1), 3-19.
[84] Lambert, J.D.; Yang, C.S. Mechanisms of cancer prevention by tea
constituents. J. Nutr., 2003, 133(10), 3262S-3267S.
[85] Lim, Y.C.; Cha, Y.Y. Epigallocatechin-3-gallate induces growth
inhibition and apoptosis of human anaplastic thyroid carcinoma
cells through suppression of EGFR/ERK pathway and cyclin
B1/CDK1 complex. J. Surg. Oncol., 2011, 104(7), 776-780.
[86] Ma, Y.C.; Li, C.; Gao, F.; Xu, Y.; Jiang, Z.B.; Liu, J.X.; Jin, L.Y.
Epigallocatechin gallate inhibits the growth of human lung cancer
by directly targeting the EGFR signaling pathway. Oncol. Rep.,
2014, 31(3), 1343-1349.
[87] Sah, J.F.; Balasubramanian, S.; Eckert, R.L.; Rorke, E.A.
Epigallocatechin-3-gallate inhibits epidermal growth factor
receptor signaling pathway evidence for direct inhibition of
ERK1/2 and AKT kinases. J. Biol. Chem., 2004, 279(13), 12755-
12762.
[88] Altomare, D.A.; Testa, J.R. Perturbations of the AKT signaling
pathway in human cancer. Oncogene, 2005, 24(50), 7455-7464.
[89] Shankar, S.; Chen, Q.; Srivastava, R.K. Inhibition of PI3K/AKT
and MEK/ERK pathways act synergistically to enhance
antiangiogenic effects of EGCG through activation of FOXO
transcription factor. J. Mol. Signal., 2008, 3(7), 1-11.
[90] Fingert, H.J.; Chang, J.D.; Pardee, A.B. Cytotoxic, cell cycle, and
chromosomal effects of methylxanthines in human tumor cells
treated with alkylating agents. Cancer Res., 1986, 46(5), 2463-2467.
[91] Lu, Q.Y.; Jin, Y.S.; Pantuck, A.; Zhang, Z.F.; Heber, D.;
Belldegrun, A.; Brooks, M.; Figlin, R.; Rao, J. Green tea extract
modulates actin remodeling via Rho activity in an in vitro multistep
carcinogenic model. Clin. Cancer Res., 2005, 11(4), 1675-1683.
[92] Sánchez-del-Campo, L.; Otón, F.; Tárraga, A.; Cabezas-Herrera, J.;
Chazarra, S.; Rodríguez-López, J.N. Synthesis and biological
activity of a 3, 4, 5-trimethoxybenzoyl ester analogue of
epicatechin-3-gallate. J. Med. Chem., 2008, 51(7), 2018-2026.
[93] Zaveri, N.T. Synthesis of a 3,4,5-trimethoxybenzoyl ester analogue
of epigallocatechin-3-gallate (EGCG): a potential route to the
natural product green tea catechin, EGCG. Org. Lett., 2001, 3(6),
843-846.
[94] Landis-Piwowar, K.R.; Kuhn, D.J.; Wan, S.B.; Chen, D.; Chan,
T.H.; Dou, Q.P. Evaluation of proteasome-inhibitory and apoptosis-
inducing potencies of novel (-)-EGCG analogs and their prodrugs.
Int. J. Mol. Med., 2005, 15(4), 735-742.
[95] Kuhn, D.; Lam, W.H.; Kazi, A.; Daniel, K.G.; Song, S.; Chow, L.;
Chan, T.H.; Dou, Q.P. Synthetic peracetate tea polyphenols as
potent proteasome inhibitors and apoptosis inducers in human
cancer cells. Front. Biosci., 2005, 10(2), 1010-1023.
[96] Fukuhara, K.; Nakanishi, I.; Kansui, H.; Sugiyama, E.; Kimura, M.;
Shimada, T.; Urano, S.; Yamaguchi, K.; Miyata, N. Enhanced
radical-scavenging activity of a planar catechin analogue. J. Am.
Chem. Soc., 2002, 124(21), 5952-5953.
[97] SáezAyala, M.; SánchezdelCampo, L.; Montenegro, M.F.;
Chazarra, S.; Tárraga, A.; CabezasHerrera, J.; RodríguezLópez,
J.N. Comparison of a pair of synthetic teacatechinderived
epimers: Synthesis, Antifolate Activity, and TyrosinaseMediated
activation in melanoma. Chem. Med. Chem., 2011, 6(3), 440-449.
Received: June 01, 2014 Revised: October 03, 20 14 Accepted: October 06, 2014