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Plant extracts have been widely used as topical applications for wound-healing, anti-aging, and disease treatments. Examples of these include ginkgo biloba, echinacea, ginseng, grape seed, green tea, lemon, lavender, rosemary, thuja, sarsaparilla, soy, prickly pear, sagebrush, jojoba, aloe vera, allantoin, feverwort, bloodroot, apache plume, and papaya. These plants share a common character: they all produce flavonoid compounds with phenolic structures. These phytochemicals are highly reactive with other compounds, such as reactive oxygen species and biologic macromolecules, to neutralize free radicals or initiate biological effects. A short list of phenolic phytochemicals with promising properties to benefit human health includes a group of polyphenol compounds, called catechins, found in green tea. This article summarizes the findings of studies using green tea polyphenols as chemopreventive, natural healing, and anti-aging agents for human skin, and discusses possible mechanisms of action.
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Green tea and the skin
Stephen Hsu, PhD
Augusta, Georgia
Plant extracts have been widely used as topical applications for wound-healing, anti-aging, and disease
treatments. Examples of these include ginkgo biloba, echinacea, ginseng, grape seed, green tea, lemon,
lavender, rosemary, thuja, sarsaparilla, soy, prickly pear, sagebrush, jojoba, aloe vera, allantoin, feverwort,
bloodroot, apache plume, and papaya. These plants share a common character: they all produce flavonoid
compounds with phenolic structures. These phytochemicals are highly reactive with other compounds,
such as reactive oxygen species and biologic macromolecules, to neutralize free radicals or initiate
biological effects. A short list of phenolic phytochemicals with promising properties to benefit human
health includes a group of polyphenol compounds, called catechins, found in green tea. This article
summarizes the findings of studies using green tea polyphenols as chemopreventive, natural healing, and
anti-aging agents for human skin, and discusses possible mechanisms of action. ( J Am Acad Dermatol
A5-year skin-cancer prevention and education
campaign sponsored by the US Department
of Health and Human Services and the
Centers for Disease Control and Prevention (CDC)
ended in May 2003. During this period, skin cancer
incidence in the United States had climbed to more
than 1 million cases per annum, rendering skin
cancer the most common type of neoplasm in the
United States.
Unfortunately, unprotected ultravio-
let (UV) exposure, the most preventable risk factor,
continues to cause increasing numbers of skin
cancers in the population. Because of the rapid
increase in skin cancer incidence, the search for
nontoxic and effective agents to protect the skin
against solar irradiation (ie, UVA, UVB) has acceler-
ated during the past 2 decades. Scientists searching
for more active approaches to protect skin using
plant-derived compounds identified the polypheno-
lic fraction of green tea as a prime candidate.
the second-most popular beverage next to water,
was found to be beneficial to the skin when applied
topically. There have been more than 150 reports of
in vivo and in vitro studies on the effects of green
tea on the skin (PubMed search; key words ‘‘green
tea’’ and ‘‘skin’’). The early focus of these studies
was chemoprevention of chemical carcinogenesis
or photocarcinogenesis in rodents. It was found
that green tea extracts or an individual green tea
polyphenol (GTPP), especially (ÿ)-epigallocatechin
(EGC)-3-gallate (EGCG), inhibited two-stage
chemical carcinogenesis (eg, induced by 7,12-di-
methylbenz(a)anthracene [DMBA] and 12-O-tetra-
decanoylphorbol 13-acetate [TPA]), and
photocarcinogenesis (induced by UVB).
In addition
to skin, studies in rodent models demonstrated that
carcinogenesis in other organs, such as lung, stom-
ach, breast, oral cavity, esophagus, pancreas, pros-
tate, duodenum, and colon, was also inhibited by
The molecular targets for GTPPs include
Ras and activator protein (AP)-1, elements of the
mitogen-activated protein kinase (MAPK) signaling
Recently, the properties of GTPPs for anti-
inflammatory, antiaging, and wound-healing effects
were also explored.
Evidence generated from
basic science laboratories indicated that GTPPs are
not only a group of reactive oxygen species (ROS)
scavengers that function as antioxidants in the epi-
dermis, but also act as modulators of different gene
groups and signal pathways. This review article
examines the progress in research on green tea
for skin protection and improvement, discusses the
possible mechanisms involved in signaling and the
various factors regulated by GTPPs, and extends an
outlook to future directions in this field. However,
epidemiologic and human studies have so far not
generated conclusive results, which may be a result
From the Department of Oral Biology and Maxillofacial Pathology,
School of Dentistry, Medical College of Georgia.
Supported by the National Cancer Institute (R21 CA097258-02)
and by funding through the Department of Oral Biology and
Maxillofacial Pathology, School of Dentistry, Medical College of
Conflicts of interest: None identified.
Accepted for publication December 21, 2004.
Reprint requests: Stephen Hsu, PhD, AD1443 School of Dentistry,
Medical College of Georgia, Augusta, GA 30912-1126. E-mail:
ª2005 by the American Academy of Dermatology, Inc.
of multiple factors, such as the conditions used in
animal studies versus human green tea consumption,
and different bioavailabilities between human
beings and rodents.
The tea plant (Camellia sinensis) has been culti-
vated in Asia for thousands of years. Currently, more
than two thirds of the world population consumes
this popular beverage. However, the majority of
the tea consumed in the world is black tea (78%),
whereas green tea consumption comprises only
China is the second largest tea producer in
the world, but is the largest producer and consumer
of green tea. The unique feature of green tea pro-
duction is that the processing of the tea leaves does
not involve any form of fermentation. Freshly picked
tea leaves are briefly heated in a pan or by steam
without any additives. The brief heating inactivates
polyphenol oxidase, thereby preserving the antiox-
idant activities of the polyphenols. The 4 major
polyphenolic catechins present in green tea leaves
are (2)-epicatechin (EC), EGC, (2)-EC-3-gallate, and
EGCG, which is the most abundant.
The total
content of polyphenols in tea leaves varies from
approximately 20% to 40%, depending on the sub-
species of the plant and geographic location. The
polyphenols are readily extracted from green tea
leaves by water or organic solvents such as methanol
and ethanol.
In contrast, production of black tea involves many
more steps, such as withering and fermentation
(oxidation). These steps ensure the enzymatic oxi-
dation of the polyphenolic catechins. Oxidation
converts these polyphenols to theaflavins and the-
arubigins, which make the taste and aroma of black
tea more appealing to most consumers in the West.
Tea consumption (mostly green tea) in China is 330
g/person/annum, which converts to about one
cup/person/d (China’s Ministry of Agriculture, June
5, 2004). Statistically, green teaeconsuming popu-
lations in China and Japan have much lower inci-
dences of certain cancers compared with nongreen
teaeconsuming populations. Comparison of the
United States and China reveals glaring facts: the
Chinese male population has a much lower inci-
dence of oral cancer, bladder cancer, prostate cancer,
and colon cancer. In particular, given the fact that the
Chinese population ranks number one in smoking,
with 350 million cigarette smokers, more than one
fourth of the total world smoking population
(China’s Ministry of Health, December 2, 2004), the
incidence of digestive and urinary tract cancers is still
remarkably low. A similarly lower incidence is found
in Japan, another green teaeconsuming and heavy-
smoking population.
These facts suggest that
green tea consumption may protect the epithelial
surface from carcinogenesis in human beings.
Skin has the largest epithelial surface of all organs,
and skin cancer is the most common type of cancer
in the United States according to the CDC.
ing melanoma, the incidence of basal cell carcinoma
and squamous cell carcinoma of skin is estimated to
exceed 1 million per year.
On the other hand, skin
cancers are among the most preventable, because
the primary cause of these malignancies is shortwave
UV radiation from the sun. GTPPs were first found to
prevent skin cancer in a chemical-induced skin-
cancer model. During the late 1980s, a group headed
by Hasan Mukhtar
at Case Western Reserve Uni-
versity (Cleveland, Ohio) applied GTPPs topically on
Sencar mice at a dose of 24 mg/mouse for 7 days
before exposure to a single dose of 200 nmol of the
initiating agent, (1/2)-7 b,8a-dihydroxy-9 a,10 a-
epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. This was
followed by topical applications twice weekly of the
tumor promoter TPA. Results showed that GTPPs
had a significant inhibitory effect on tumor induction
in this initiation-promotion model.
These investi-
gators also tested topical application of GTPPs in a
complete skin tumorigenesis protocol using 3-meth-
ylcholanthrene on BALB/c mice, and a two-stage
skin tumorigenesis protocol using DMBA as the
initiating agent and TPA as tumor promoter with
Sencar mice. Significant protection by GTPPs against
skin tumorigenicity was demonstrated.
These find-
ings represent the first topical application of GTPPs
for protection from skin cancer and served as a
foundation for subsequent studies. A mechanistic
study of GTPPs’ protective effect followed, which
showed that the antioxidant activity of GTPPs could
be responsible for the anticarcinogenic potential
against TPA and free radicals.
It was later found
that EGCG was a potent anticarcinogen in a chem-
ically induced cutaneous cancer model. EGCG sig-
nificantly inhibited binding of
H-labeled polycyclic
aromatic hydrocarbons to epidermal DNA. Topical
pretreatment of mice with EGCG resulted in signif-
icant reduction in tumor size and number per mouse
in a DMBA tumor-initiation model.
The first UVB radiation-induced photocarcino-
genesis study using GTPPs as a protection agent was
reported 2 years later by Mukhtar and colleagues.
Female SKH-1 hairless mice were either fed 0.1%
GTPPs or GTPPs were topically applied, followed
by exposure to UVB radiation. Both applications
afforded photoprotection against UVB. Thus, a new
JUNE 2005
1050 Hsu
era of studying skin-cancer prevention by phyto-
chemicals present in a popular beverage had
UV protection was the main focus for earlier
animal studies of green tea extracts.
Using hairless
mice, oral consumption or topical application of
brewed green tea, green tea extracts, or GTPPs
showed significant protection against UV or chem-
ical-induced carcinogenesis. One of the earlier stud-
ies used brewed green tea as the sole fluid source for
SKH-1 mice during carcinogenesis initiated by either
UVB or DMBA and promoted by either TPA or UVB,
respectively. Oral consumption of brewed green tea
at concentrations similar to human consumption
(1.25% and 2.5%) significantly inhibited UVB- or
TPA-induced tumorigenesis.
This group, led by
at Rutgers University, later found that
oral administration of decaffeinated green tea pos-
sesses similar anticarcinogenic effects. They later
showed that green tea oral administration in mice
not only inhibited skin tumorigenesis but also re-
duced fatty tissues in the dermis.
oral administration of GTPPs resulted in decreased
UVB-induced ornithine decarboxylase and cyclo-
oxygenase (COX) activities.
Oral administration
or intraperitoneal injection of GTPPs could achieve
similar effects to inhibit the growth of UV-induced
skin papillomas
or TPA-induced COX2 in rodent
In models of topical application, GTPPs inhibited
DMBA-initiated, TPA-induced carcinogenesis and
benzo[a]pyrene- and TPA-induced tumor initiation
in CD-1 mice.
Topical application of GTPPs
reduced TPA-induced inflammation, ornithine de-
carboxylase activity, hyperplasia, and hydrogen per-
oxide (H
) formation, suggesting GTPPs serve as
both an antioxidant and a regulator of enzymatic
TPA-induced elevation of COX and li-
poxygenase were significantly inhibited by topical
application of GTPPs to Sencar mice,
and EGCG
was found to be the most effective agent tested in
reducing epidermal ornithine decarboxylase activity
induced by chemical tumor promoters.
It appears that GTPPs provide a shield effect
against photocarcinogen-induced oxidative stress.
Topical application of GTPPs (5 mg/animal) or
EGCG (1 mg/cm
of skin) before UVB exposure in
SKH-1 hairless mice significantly prevented UVB-
induced depletion of the antioxidant enzymes
glutathione peroxidase, catalase, and glutathione;
inhibited UVB-induced oxidation as measured by
lipid peroxidation and protein oxidation; and in-
hibited UVB activation of MAPK family members
extracellular signal-regulated kinase (ERK) 1 and 2,
c-jun N-terminal kinase (JNK), and p38.
can be rapidly metabolized by reacting with ROS,
providing the first line of defense against ROS in vivo,
and they also inhibit pro-oxidant enzymes such as
nitric oxide synthase, lipoxygenases, COX, and xan-
thine oxidase, which provide the second line of
defense against free radicals, especially H
An interesting study used SKH-1 hairless mice,
which are at high risk for skin cancers, to mimic the
frequent exposure of UVB as a photocarcinogen.
The mice were exposed to UVB twice a week for 20
weeks before daily topical application of EGCG (6.5
mol/L) for another 18 weeks. The results showed
that EGCG decreased the number of nonmalignant
and malignant tumors per mouse by 55% and 66%,
respectively, suggesting that the effect of EGCG was
not just caused by a sunscreen/antioxidant effect. In
fact, apoptotic activities were significantly increased
in tumor cells but not in normal cells.
Oral versus topical administration of GTPPs
The animal studies discussed above suggest that
oral administration of GTPPs can provide skin pro-
tection in rodents. However, similar studies in human
beings did not achieve such effects, presumably
because the human dermis provides a stronger
barrier to absorption from the vasculature.
versely, rodents appear to possess a weaker barrier,
in that topical application of EGCG at a high con-
centration (10% in hydrophilic ointment United
States Pharmacopeia) resulted in toxicity in SKH-1
mice and formation of erythema and papular lesions
within days,
but human skin showed no side
Therefore, the effects of topical application
of GTPPs, rather than oral administration, may have a
greater clinical significance in human beings.
Compared with animal studies, evaluation of
GTPPs in human skin has been very limited. EGCG
effectively penetrates the dermal barrier in mice but
not in human beings.
In a human biopsy study,
green tea extracts and individual polyphenols were
applied topically for 30 minutes before a 2-minute
exposure to UV irradiation, and the skin samples
were analyzed by immunohistochemistry. The top-
ical application of these agents caused a dose-
dependent inhibition of the erythema response
induced by UV radiation. Green tea extracts reduced
the number of sunburn cells and DNA damage.
Among the GTPPs, EGCG and (2)-EC-3-gallate (the
polyphenols that possess a gallate group) were
effective, whereas EGC and EC (the polyphenols
Hsu 1051
that lack a gallate group) were ineffective.
EGCG at 3 mg/2.5 cm
was applied before UVB
exposure, UVB-induced erythema and UVB-induced
infiltration of leukocytes were reduced.
GTPPs could be applied for photoprevention in
human beings. Fig 1 summarized the major protec-
tive effects of GTPPs against photocarcinogenesis.
A combination of psoralen and UVA (PUVA)
therapy has been used for treatment of certain skin
diseases, such as psoriasis, to reduce toxicity that is
caused by systemic drugs.
However, prolonged
treatment with PUVA increases the risk of skin
cancer, especially squamous cell carcinoma.
study using several in vitro and in vivo models,
including human beings, found that 30-minute top-
ical application of 0.2 mg/cm
green tea extract
almost completely inhibited PUVA-induced ery-
thema; the same extract also inhibited DNA damage
caused by PUVA, suggesting that GTPPs protect
the epidermal keratinocytes from PUVA therapye
induced carcinogenesis.
Another interesting
finding was that green tea may help to protect hair
follicles from g-rayeinduced apoptosis.
A number
of human trials using GTPPs as chemopreventive
agents against skin carcinogenesis are currently
under way, targeting COX2 and the MAPK signal
pathways. The goal of these trials is to develop
formulations of agents such as GTPPs in sunscreen
and other protective skin applications for use against
UVB-induced carcinogenesis.
Differential effect in normal versus
malignant cells
Because GTPPs and EGCG were found to selec-
tively induce apoptosis in tumor cells but not normal
human epidermal keratinocyte (NHEK), in vitro
studies on the molecular mechanisms for the chemo-
preventive properties of GTPPs were initiated.
Compared with epidermoid carcinoma cells,
NHEKs showed less sensitivity to EGCG-induced
inhibition of nuclear factor (NF) kB, a prosurvival
transcription factor often up-regulated in tumor cells,
suggesting tumor cells are more susceptible to
EGCG-induced apoptosis and growth arrest.
the other hand, pretreatment of NHEKs with EGCG
suppressed UVB-induced activation of NF kBina
Fig 1. Schematic illustration of properties of green tea in photoprotection against UV
irradiation, summarized from previously published data.
Only epidermis is
shown. EGCG,(ÿ)- Epigallocatechin-3-gallate; GTP, green tea polyphenol.
JUNE 2005
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dose- and time-dependent manner.
EGCG inhibited TPA-induced NF kB in a mouse
cell line model.
It appears that this observation is
contradictory to the prosurvival effect of EGCG in
NHEKs. But it may be interpreted as the activation of
a terminal differentiation pathway, which involves a
caspase 14-mediated planned cell death. Therefore,
inhibition of the prosurvival transcription factor NF
kB might be required.
UVB protection
In human keratinocytes, EGCG inhibited UVB-
induced AP-1 expression, suggesting that AP-1, a
group of downstream transcription factors in the
MAPK pathway, including c-Fos and c-Jun, could be
a target for EGCG function.
MAPKs are important
signal transduction proteins that can be activated
through serial phosphorylation cascades and regu-
late gene expression in response to exogenous
stimuli. Depending on the stimuli, the subsequent
cellular responses induced by the downstream fac-
tors of the MAPK pathway determine the fate of a
cell through the activation of either antiapoptotic or
proapoptotic genes. In general, among the MAPK
pathways involving ERK, JNK, and p38, ERK is
activated by mitogens and growth factors, and p38
and JNK are activated by stress stimuli such as UV
irradiation or oxidants, resulting in apoptosis.
In a keratinocyte cell line HaCaT, UVB-induced c-
Fos expression was specifically inhibited by EGCG at
both the messenger RNA and protein levels. UVB-
induced activation of MAPK p38, the upstream factor
of c-Fos, was also inhibited by EGCG. However, c-
Jun activation was not modulated by EGCG, nor was
its upstream activator, JNK.
This might be a result
of the induction of p57/KIP2, a cyclin-dependent
kinase inhibitor, which binds and inhibits the activity
of JNK.
A more comprehensive study demon-
strated that pretreatment of NHEKs with EGCG
inhibited UVB-induced intracellular H
, and UV-
induced phosphorylation (activation) of ERK 1 and
2, JNK, and p38.
In addition, UVB-induced degra-
dation and phosphorylation of IkBaand activation
of IKKawere inhibited by pretreatment of EGCG for
24 hours, therefore, preventing the nuclear localiza-
tion of NF kB.
These effects could be ascribed to
EGCG’s regulatory effects on the MAPK pathway and
its antioxidant activity because EGCG is able to
scavenge ROS and bring ROS to background levels
in NHEKs.
UVA protection
UVA is another type of shortwave UV radiation.
EGC inhibited UVA-activated COX, a stress-respond-
ing gene product, in epidermoid keratinocytes,
which suggested that the effect of this GTPP may
involve direct effects on signal transduction, in
addition to its antioxidant activity.
Thus, GTPPs
appear to regulate stress-responding pathways, spe-
cifically the MAPK pathways. With respect to UVA-
induced ROS, GTPPs were effective in reducing the
toxicity caused by UVA-induced ROS in primary rat
epidermal keratinocytes, with inhibition of the UVA-
activated release of the plasma protein lactate dehy-
drogenase and up-regulation of UVA-suppressed
glutathione peroxidase activity.
In healthy primary
rat epidermal keratinocytes, GTPPs were able to
inhibit lactate dehydrogenase release and increase
glutathione peroxidase activity at a concentration
range of 0.05% to 0.1%. When cell growth and
apoptosis were measured, 0.01% to 0.1% GTPPs
stimulated cell proliferation and inhibited apoptosis,
suggesting that GTPPs may potentially benefit skin
healing by promoting keratinocyte proliferation.
As a multifunctional agent
UVB increases the levels of intracellular H
activates the MAPK pathway in NHEKs, and EGCG
inhibits them both. Pretreatment of 20 mol/L EGCG
reduced UVB-elevated H
and phosphorylation of
ERK 1 and 2, JNK, and p38 by more than 50%.
However, in addition to the photoprotection effects
from EGCG, the MAPK signal transduction pathway
regulated by EGCG in NHEKs appears to be associ-
ated with other functions, because EGCG modulates
this pathway in NHEKs in the absence of stress
inducers. In contrast to EGCG-treated tumor cell
lines, immortalized epithelial cell lines, or UV-treated
NHEKs (where EGCG/GTPP inhibited MAPK activa-
tion), EGCG increased the activities of certain
elements in the MAPK pathway in exponentially
growing NHEKs. Specific regulation by EGCG of
an AP-1-activated gene, involucrin, was reported.
Human involucrin is a marker for NHEK intermediate
to late differentiation, and its promoter can be
activated by AP-1 elements. EGCG induced the
phosphorylation of Ras, MEKK1, MEK3, and p38d
(an isoform of p38) of the MAPK signal transduction
pathway and induced AP-1 transcription factors c-
Jun and c-Fos, and other AP-1 family members, Fra-1,
Fra-2, FosB, JunB, and JunD (JNK activation was not
measured in this study). In addition, cornification of
the NHEKs was observed.
Thus, whether EGCG is
involved in NHEK differentiation became an inter-
esting issue. We reported that EGCG selectively
induced p57/KIP2, the only KIP/CIP family member
of the cyclin-dependent kinase inhibitors involved in
development. The induction of p57 by EGCG was
only found in NHEKs but not in epithelium-derived
tumor cells.
p57 is linked with the MAPK pathway
Hsu 1053
by negatively regulating JNK activation through
direct binding.
EGCG-induced p57 may modu-
late the activity of JNK to prevent caspase 3-mediated
apoptosis, because persistent activation of JNK leads
to apoptosis.
Indeed, cells that lack p57 induction
underwent caspase 3-dependent apoptosis in re-
sponse to EGCG.
It was later found that EGCG-
induced p57 was associated with rapid terminal
differentiation marked by increased expression of
keratins and filaggrin, and activated transglutamin-
ase activity within 24 hours in exponentially growing
NHEKs. On the other hand, aged NHEKs (25 days
postconfluence) showed new DNA synthesis, sug-
gesting a potential role in aged keratinocyte prolif-
eration by EGCG.
In a human study, topical
application of 10% EGCG stimulated NHEK prolifer-
ation and increased skin thickness in elderly men,
which further confirmed the possible stimulatory
effects of EGCG in the aged epidermis.
In summary, as powerful antioxidants, GTPPs
scavenge ROS produced by UV or other sources
(ie, carcinogenenic chemicals and autosynthesis
mechanisms). As active nutriceuticals, GTPPs are
able to: (1) modulate elements in the Ras-MAPK
signal pathway, including ERK, JNK, and AP-1; (2)
inhibit COX2, phase I and phase II enzymes; (3)
inhibit inflammation-related responses, such as IL-1,
IL-10, and IL-12 release; (4) activate a novel terminal
differentiation pathway associated with p57 and
caspase 14 expression, and accelerate skin barrier
formation; (5) suppress the caspase 3-mediated ap-
optosis pathway and activate caspase 14-mediated
planned cell death pathway in normal cells; and (6)
stimulate proapoptotic genes such as p53 and p21,
and suppress the activity of the prosurvival tran-
scription factor NF kB in tumor cells.
Table I lists the major effects of GTPPs found on
normal epidermal systems.
Table I. Summary of multiple effects of green tea polyphenols and the cellular/molecular responses induced
in the epidermal systems
Green tea-induced effects Cellular/molecular responses References
UV protection Inhibition of tumorigenesis;
inhibition of UV-induced MAPK
activation; inhibition of UV-induced AP-1
activation; inhibition of UVA-induced LDH;
up-regulation of UVA-suppressed GSH-Px;
inhibition of UVB-induced infiltration of
macrophages and neutrophils
5, 11, 22-26, 29, 34, 35, 37, 41,
48, 49, 54-63, 71
Antioxidant Elimination of reactive
oxygen species; stabilization
of GSH-Px, catalase,
and glutathione; inhibition
of nitric oxide
synthase, lipoxigenase, COX and
xanthine oxidase; inhibition of
lipid peroxidase
11, 31, 34-36, 60, 68, 69, 75
Anti-inflammation Inhibition of ODC, COX, lipoxigenase;
inhibition of IL-1, IL-8, IL-10 and
IL-12 release; inhibition of UVB-induced
infiltration of macrophages and
28, 31, 33, 70-73
Acceleration of keratinocyte
differentiation and wound
Induction of p57, filaggrin,
keratins, involucrin
and transglutaminase activity;
induction of caspase 14
12, 31, 57, 64, 88
Anticarcinogen Inhibition of tumorigenesis;
inhibition of carcinogen-DNA binding
18-21, 30-33, 74
Protection of PUVA-induced
Inhibition of erythema
and DNA damage
45, 46
Protection of hair
follicles from radiation
Inhibition of radiation-induced apoptosis 47
AP, Activator protein; COX, cyclonoxygenase; GSH-Px, glutathione peroxidase; LDH, lactate dehydrogenase; MAPK, mitogen-activated protein
kinase; PUVA, psoralen plus ultraviolet A light.
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1054 Hsu
Green tea and EGCG effectively scavenged UV-
induced reactive ROS, therefore, protecting DNA
from UV-induced damage.
In addition, EGCG at
3 mg/animal prevented UVB-induced IL-10 produc-
tion in the skin, indicating the ability of modulating
the immune response by EGCG.
A cell surface
marker, CD11b, for activated macrophages and
neutrophils was decreased by EGCG in animals
treated with UVB, suggesting an inhibition of UVB-
induced infiltration of these cells associated with
immune suppression.
In addition, tumor necrosis
factor a-induced IL-8 release was dose-dependently
inhibited by EGCG in cultured NHEKs, whereas
vascular epithelial growth factor was stimulated.
Another study demonstrated that TPA-induced IL-1
expression was significantly inhibited by GTPPs.
In mouse epidermal cells, EGCG inhibited TPA-
induced NF kB activation by blocking phosphoryl-
ation of IkBa(inhibitor of NF kB) at Ser32 and
inhibited the DNA binding of NF kB.
The protective
properties of GTPPs against UV-irradiation possess
potential value for antiaging purposes, especially
for the prevention of photoaging, which causes
roughness and sagginess of the skin. In a study using
a combination of guinea pigs, hairless mice, and
human dermal fibroblast cultures, EGCG was found
to reduce the UVB-induced lipid peroxide level by 3-
fold, prevented UVA-induced skin damage (rough-
ness and sagginess), and inhibited the expression of
collagenase in cultured human epidermal fibroblasts
and the promoter-binding activities of AP-1 and NF
Oxidative damage induced by UVB may also
cause modifications of proteins, eg, collagen cross-
linking and formation of carbonyl derivatives, which
Fig 2. Expression of green tea targeted genes in response to (ÿ)- epigallocatechin-3-gallate
(EGCG) exposure in human epidermal keratinocytes, based on previously published
Certain cell growth regulating genes are inhibited, major markers for
keratinocyte differentiation are up-regulated, whereas many genes coded for proapoptosis
factors are suppressed. Only epidermis is shown. AMD1, S-adenosylmethionine decarboxylase
1; CARD, caspase recruitment domain; COX 2, cyclooxygenase-2; EGF, epidermal growth
factor; EGF-R, epidermal growth factorereceptor; EPS8, a substrate for the epidermal growth
factor receptor kinase; FGF2, fibroblast growth factor 2; GADD45b, growth arrest and DNA
damage 45b; GTP, green tea polyphenol; HSP70, heat-shock protein 70; ODC, ornithine
decarboxylase; Rb, retinoblastoma; TNF-R, tumor necrosis factor receptor; TRADD, tumor
necrosis factor receptor 1 (TNFR1)eassociated death domain protein; VEGF-R2, vascular
epithelial growth factor-receptor 2.
Hsu 1055
can be measured by a fluorescence assay and the
reduction reaction method. A study using C57BL/6
mice found that collagen cross-linking could be
reduced by a green tea extract at 10 months of age.
In addition to anticancer and photoprotection
potentials, green tea may provide alternative treat-
ment for other skin disorders. In the epidermis,
keratinocytes exist in various stages of differentia-
Abnormalities in any of the programmed
differentiation events may lead to epidermal disor-
ders, such as psoriasis and skin cancer. However,
biologic events that enable basal cells (stem cells)
to proliferate, differentiate, and commit planned cell
are still poorly understood.
differentiation can be accelerated by prodifferentia-
tion agents such as extracellular calcium and reti-
noids, but cancer cells derived from the epidermal
epithelium lose the ability to respond to the prodif-
ferentiation agents.
Abnormal, or lack of, differen-
tiation also can be found in other skin disorders, such
as psoriasis, actinic keratosis, cherry angiomas,
Bateman’s purpura, chondrodermatitis nodularis
helicis, seborrehic keratosis, and rosacea. In these
skin disorders, the skin barrier is often disrupted.
A caspase family member, caspase 14, was iden-
tified in 1998 from murine tissues, and found only
in epithelial tissues, especially in the differentiating
Unlike the other caspases, caspase 14
is not involved in the well-documented apoptotic
caspase cascade, but is associated with terminal
differentiation of NHEKs and skin barrier forma-
Transcriptional activation of caspase 14
was found during stratum corneum formation.
Caspase 14 expression was diminished on inhibition
of cell differentiation.
Therefore, caspase 14 is
believed to facilitate epidermal differentiation, pos-
sibly activating planned cell death and cornification
of the epidermal keratinocytes to form the skin
barrier. In contrast, in pathologic conditions such
as psoriasis, in which cornification is altered, the
normal expression pattern of caspase 14 is absent.
In our recent studies, we found that EGCG
activates a coordinated expression of p57 and
caspase 14 in NHEKs, which facilitates terminal dif-
ferentiation in these cells. In contrast, a squamous
cell carcinoma cell line OSC2 and salivary cancer cell
line HSG, and human psoriatic keratinocytes, only
exhibit basal levels of caspase 14. This study led to
our finding that EGCG is able to induce caspase 14
expression in exponentially growing NHEKs within
24 hours, subsequent to p57 induction,
but human
psoriatic tissue lacks nuclear translocation of caspase
Psoriasis has been considered to be an immu-
nologic phenomenon. However, phenotypically it
manifests as an epithelial disorder with abnormal
morphologic and functional features. In this regard,
our observation that psoriatic keratinocytes lack the
nuclear entry of caspase 14 might be linked to the
failure of cornification and appropriate barrier for-
mation in psoriatic keratinocytes. Thus, induction of
caspase 14 expression and nuclear localization by
green tea may promote differentiation and skin
barrier formation, which may lead to new treatments
for skin disorders that lack normal differentiation.
The green teaeregulated gene expressions in accel-
erating epidermal keratinocyte differentiation are
profiled in Fig 2. Combined with other properties
of green tea, such as stimulation of aged keratino-
cytes and inhibition of apoptosis, green tea may
assist the healing process in the epidermis when
applied topically.
Although the majority of the evidence shows
remarkable benefits of antioxidant, anticancer, anti-
aging, and anti-inflammation effects from green tea
constituents, standard delivery systems for topical
application of GTPPs have not been established. This
is partially because of the nature of these highly
reactive compounds, which are easily oxidized in the
environment and gradually lose their activities if not
used immediately after preparation. Therefore, the
primary goal for a topical formulation is to maintain
the stability of these antioxidants. A preformulation
study of EGCG concluded that multiple factors
should be considered with regard to the stability
issue and that EGCG is rapidly degraded if it is in
an aqueous formulation. Thus, although potential
synergistic effects must be evaluated, simple mixing
of EGCG or GTPPs with other antioxidants may
not increase stability.
An earlier study that tested
10% EGCG in hydrophilic ointment United States
Pharmacopeia suggested that addition of 0.1% bu-
tylated hydroxytoluene to this formulation boosted
the stability significantly.
These types of formula-
tions, with combined active compounds, are still to
be evaluated in human trials. Therefore, the stability
issue of GTPPs for topical application remains to be
The second challenge is the epidermal penetra-
tion. With the exceptions of abnormal conditions
such as traumatic open wounds, infections, or path-
ologic lesions, human skin is a waterproof barrier
protected by multilayers of cornified keratinocytes.
The hydrophilic GTPPs in an aqueous phase of a
formulation, regardless of stability, may have to rely
on high concentration to penetrate this barrier
JUNE 2005
1056 Hsu
and achieve effectiveness, as previously shown.
However, recent tests using in vitro delivery models
demonstrated that solutions saturated with green
tea extract, or adhesive patches with more than
1 mg/cm
green tea extract failed to deliver the
polyphenols, after a 24-hour period, in a concentra-
tion higher than the maximum serum concentration
(\10 mol/L).
On the other hand, a high concen-
tration of EGCG, such as 10%, has not been tested for
long-term toxicity. In addition, high concentrations
of GTPPs or EGCG in a formulation would consid-
erably increase the cost. Therefore, approaches
other than simply increasing the concentration of
GTPPs or EGCG may be required as alternative
strategies. For example, changing the physical prop-
erties of GTPPs by molecular modification to in-
crease the stability and improve skin penetration
may be an option. Taken together, the 3 major
challenges, ie, stability, penetration, and cost, need
to be addressed to effectively bring the benefits of
green tea to the human skin.
The author thanks Drs Douglas Walsh, Baldev Singh,
Douglas Dickinson, and Wendy Bollag for their valuable
comments and Dr Rhea-Beth Markowitz for scientific
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Hsu 1059
... Curcumin also act as an antioxidant, suppress ROS production, scavenge free oxygen radicals and inhibit lipid12 peroxidation. GREEN TEA: Topical or oral administration og green tea leads to inhibition of chemical carcinogens and UV radiation-induced skin.20 carcinogenesis Green tea acts as an antioxidant and ROS scavenger in the epidermis to reduce the number of sun burn cells, DNA damage and20 antiaging. There are 2 active molecules in green tea; green tea polyphenol (GTPP) epigallocatechin (EGC)-3-gallate (EGCG). ...
... There are 2 active molecules in green tea; green tea polyphenol (GTPP) epigallocatechin (EGC)-3-gallate (EGCG). These molecules were20 found to inhibit chemical carcinogenesis. In humans, topical application of green tea is not 20 effective due to poor epidermal penetration. ...
Full-text available
The concept of anti-aging is becoming more popular. This is because more individuals are living longer. The world is becoming increasingly cosmetic with increasing interest in appearance and the subject of slowing down aging is increasingly becoming the focus of scientific research. Now, aging is no longer accepted as 'natural' as there are ways to influence it. The role of nutrition as a tool for anti-aging has become topical. This subject of the use of food for nutritional and medicinal purposes is referred to as nutraceuticals. Nutraceuticals function as antioxidants, lipid membrane stabilizers, enzyme inducers or inhibitors. The role of nutraceuticals in anti-aging is hereby presented.
... A range of herbal medicines are progressively used to treat respiratory infections and inflammatory diseases [47,48], yet whether other plants would evoke more beneficial effects than ginger or mustard when applied as chest compresses still requires investigation. Interestingly, most Evidence-Based Complementary and Alternative Medicine plants with anti-inflammatory and antioxidant properties produce flavonoid compounds with phenolic structures [49,50]. Promising results are reported for catechins, the polyphenolic flavonoids of green tea [49], which provide antiviral, antibacterial, anti-inflammatory, and antioxidant activities [51]. ...
... Interestingly, most Evidence-Based Complementary and Alternative Medicine plants with anti-inflammatory and antioxidant properties produce flavonoid compounds with phenolic structures [49,50]. Promising results are reported for catechins, the polyphenolic flavonoids of green tea [49], which provide antiviral, antibacterial, anti-inflammatory, and antioxidant activities [51]. Scientific evidence suggests a pathogenic role of free radical damage in respiratory tract infections, which is why substances with antioxidant activity can help to reduce both oxidative stress and inflammation [51]. ...
Full-text available
Background. Chest compresses with mustard (MU) or ginger (GI) are a complementary treatment option for respiratory tract infections. However, little is known about their specific thermogenic qualities. This study examines the short-term effects of MU, GI, and chest compresses with warm water only (WA) on measurable and self-perceived body warmth in healthy adults. Methods. This was a single-center, randomized controlled trial with cross-over design (WA versus MU versus GI). 18 participants (23.7 ± 3.4 years; 66.7% female) received MU, GI, and WA in a random order on three different days with a mean washout period of 13.9 days. Chest compresses were applied to the thoracic back for a maximum of 20 minutes. The primary outcome measure was skin temperature of the posterior trunk (measured by infrared thermography) immediately following removal of the compresses (t1). Secondary outcome measures included skin temperature of the posterior trunk 10 minutes later (t2) and several parameters of self-perceived warmth at t1 and t2 (assessed with the Herdecke Warmth Perception Questionnaire). Results. Skin temperature of the posterior trunk was significantly higher with MU compared to WA and GI at t1 (p
... (-)-Epigallocathechin gallate, 2) (-)-EGC: (-)-Epigallo cathechin, 3) (-)-ECG:(-)-Epicatechingallate,and4)(-)-EC:(-)-Epicatechin. [1][2][3][4] One study revealed that the antioxidant activity of catechins, especially EGCG and ECG, was stronger than that of vitamins C and E. 5 There werecellularstudiesthatrevealedthatEGCGdecreasedtypeIcollagen degradation through several mechanisms. A study reported that EGCG suppressed the activities of the gelatinases (MMP-2 and MMP-9) and collagenase, as well as augmented the expressions of the tissue inhibitor of metalloproteinase-1(TIMP-1) more than retinoic acid. ...
Introduction The bioactivities of green tea extract were indicated to promote skin health in vitro. Few clinical studies reported on skin nourishment of topical applying green tea extract due to the limited skin absorption. Methods This current study evaluated the clinical effectiveness and safety of green tea extract encapsulated chitosan microparticles (GTP) in emulsion base on a split-face, double-blind, randomized placebo-controlled study. Twenty-nine female volunteers were recruited into the study. They were randomly assigned to apply GTP and placebo creams on each half face for 8 weeks. The facial skin properties on both sides were monitored and evaluated every 2 weeks. Results The results revealed that skin elasticity (R2) of half face treated with GTP cream (0.748 ± 0.05) was superior to another that received placebo cream (0.722 ± 0.05) at 4th week. In addition, melanin index implying skin dullness of the half face that received GTP cream significantly improved within the 6th week after application (placebo =295.60 ± 58.81, GTP =282.70 ± 59.62). Most importantly, the photographs clearly indicated that the decreasing in facial wrinkles of volunteers applied with GTP cream was more than those applying placebo cream. Signs of skin irritation were not evident in both treatment and placebo cream groups. Conclusion Based on study outcomes, the green tea extract encapsulated chitosan microparticles appear to be the promising active candidate for promoting skin elasticity and improving skin dullness and wrinkles.
A cosmetic is a formulation containing substances of natural or artificial origin intended to boost the appearance of any part of the body for which it is designed to gain the esthetic appeal to the members of the audience. Such products are meant for use on the face to supplement one’s appearance and are often designated as makeup. Several undesirable effects are concomitant to synthetically based cosmetics owing to their content of harmful synthetic ingredients. Attention has then been shifted toward herbal bioactive-based cosmetics containing phytoconstituents possessing antioxidant and free-radical scavenging actions exploited to control skin disorders like dry skin, eczema, ageing, inflammations, etc., and in aromatherapy. Cosmetics appear as solids, semisolids, or liquids and in a broad sense, could be formulated as solutions, creams/emulsions, lotions, suspensions, ointments, pastes, powders, gels, sticks, pencils, tablets, capsules, or aerosols. They can be itemized according to the part of the body they are meant to be used at, such as products for the skin, hair, nails, teeth, and eye or on the basis of their function as emollients, cleansing, decorative, deodorant/antiperspirants, and protective preparations. Herbal bioactive ingredients suitable for preparing cosmetics could be extracted from various parts of organic materials, especially plants that are in abundance. With innovations in research and development and technology, these phytoconstituents are standardized and their novel products are patentable. The future and market for herbal bioactive-based cosmetics are high.
Tea polyphenols (TP), which is accounting for 15-30% of the dry weight of green tea and are widely used in the food industry as antioxidants, preservatives, color preservatives, and flavoring agents. To determine the concentration of TP, a fluorescent method based on nitrogen and chlorine co-doped carbon dots (R-CDs) was investigated. The R-CDs we prepared showed red emission with an absolute quantum yield (QY) of approximately 16.67 ± 0.85%. The limit of detection (LOD) was calculated to be approximately 68 ± 0.94 ng/mL, with an R² of 0.999 over the TP range of 1-20 μg/mL. Compared to the ferrous tartrate standard curve method, the concentration of TP in green tea, which was purchased from the market, detected using our method showed an error within 5%, indicating good potential applications in the food industry. Cell imaging experiments suggested that the R-CDs exhibit excellent lysosomal targeting as the Pearson’s correlation coefficient (PCC) in colocalization analysis was found to be 0.91. Further experiments showed that owing to their excitation-independent emission and high QY, the R-CDs could be applied to not only for detecting TP content but also for targeting lysosomes as substitute for commercial dyes.
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Wound healing is a complex and dynamic cellular process to restore tissue function. Current treatments for chronic wounds especially diabetic ulcers are expensive, with adverse effects. Recently, numerous researchers have focused on the potential effect of natural products on wound healing. One of them is mangosteen (Garcinia mangostana Linn). It is a well-known tropical fruit that is native to Southeast Asia. The active ingredient of mangosteen pericarp contains xanthones that exhibit a wide range of pharmacological activities, including anti-inflammatory and anti-bacterial properties which are the core elements needed in wound healing. Firstly, this review discusses the concepts of abnormal and normal wound healing mechanisms. Then an in depth observation of the pharmacological activities of mangosteen and its derivatives was presented to study their potentially beneficial applications in the treatment of chronic wound healing which is a contemporary medical issue.
The recovery of skin wounds is a complex biological process involving three basic mechanisms: inflammatory phase, re-epithelialization followed by granulation and tissue remodeling. The interactions between inflammatory cells, fibroblasts, and keratinocytes induce microenvironmental changes at the wound site. Tissue remodeling is initiated by matrix-producing proteins and protease enzymes and collagen fibers in the dermis. A saponin extracted from ginseng, known as ginsenoside, has been shown to accelerate neovascularization in burn wounds in mice. It also increases levels of vascular endothelial growth factor and interleukin (IL-β). IL-β accelerate wound healing by promoting accumulation of macrophages at skin wound sites. Saponins are major active constituents of ginseng. They contain many ginsenosides. The purified ginsenosides or the extracts of ginseng root have been reported to have beneficial effects on damaged skin. For instance, red ginseng root extract protected skin from acute UVB-irradiation. Ginsenoside F1, an enzymatically modified derivative of the ginsenoside Rg1, protected HaCaT against UVB-induced apoptosis. Panax ginseng root extract promotes type I collagen synthesis in human dermal fibroblasts (HDF) via the Smad activation pathway and exhibits antioxidant activity against free radicles including diphenyl-p-picrylhydrazyl treatment. In addition, ginsenoside Rb1 promotes healing process of burn wound by enhancing angiogenesis. Among the various ginsenosides, ginsenoside Rb1 has been found to most potent agent for wound healing.
Ginseng is the most well-known Chinese medicine, as well as one of the most commonly used herbal medicines having a wide range of medical and pharmacological uses. The botanical description and complexity of "Ginseng" species, phytochemistry, traditional and biotechnological production systems, traditional usage, current applications, and future directions for the development of ginseng compounds as effective medicinal agents are covered in this book.
There has been considerable research in recent years on dietary factors and/or nutritional elements that might impact melanoma risk. A wide variety of dietary compounds have been studied, but only a selected group will be discussed in this review. Many have promising in vitro evidence supporting their potential, and some have been associated with decreased melanoma risk in epidemiologic studies; however, data from randomized controlled trials in humans are lacking. Future studies may be able to clarify the potential role of dietary components in melanoma risk reduction.
The tea plant Camellia sinesis is cultivated in >30 countries. Epidemiologic observations and laboratory studies have indicated that polyphenolic compounds present in tea may reduce the risk of a variety of illnesses, including cancer and coronary heart disease. Most studies involved green tea, however; only a few evaluated black tea. Results from studies in rats, mice, and hamsters showed that tea consumption protects against lung, forestomach, esophagus, duodenum, pancreas, liver, breast, colon, and skin cancers induced by chemical carcinogens. Other studies showed the preventive effect of green tea consumption against atherosclerosis and coronary heart disease, high blood cholesterol concentrations, and high blood pressure. Because the epidemiologic studies and research findings in laboratory animals have shown the chemopreventive potential of tea polyphenols in cancer, the usefulness of tea polyphenols for humans should be evaluated in clinical trials. One such phase 1 clinical trial is currently under way at the MD Anderson Cancer Center in collaboration with Memorial Sloan-Kettering Cancer Center. This study will examine the safety and possible efficacy of consuming the equivalent of ≥10 cups (≥2.4 L) of green tea per day. The usefulness of tea polyphenols may be extended by combining them with other consumer products such as food items and vitamin supplements. This “designer-item” approach may be useful for human populations, but it requires further study.
Conference Paper
Oral administration of green tea or caffeine to hairless SKH-1 mice for 2 weeks stimulated UV-induced increases in apoptotic sunburn cells in the epidermis, and a similar effect was observed when caffeine was applied topically immediately after UV. In mice pretreated with UV for 22 weeks (high-risk mice without tumors), topical applications of caffeine 5 days a week for 18 weeks with no further UV treatment inhibited carcinogenesis and stimulated apoptosis in the tumors. Oral administration of green or black tea to UV-pretreated high-risk mice for 23 weeks inhibited skin tumorigenesis, decreased the size of the parametrial fat pads and decreased the thickness of the dermal fat layer away from tumors and directly under tumors. Administration of the decaffeinated teas had little or no effect on these parameters and adding caffeine to the decaffeinated teas restored their inhibitory effects. Administration of caffeine alone also inhibited carcinogenesis and decreased the size of the parametrial fat pads and the thickness of the dermal fat layer. Using data from individual mice and linear regression analysis, we found a highly significant positive correlation between the thickness of the dermal fat layer away from tumors and the number of tumors per mouse. (C) 2002 Lippincott Williams Wilkins.
Conference Paper
Green tea polyphenols are reported to possess substantial antiinflammatory and chemopreventive properties. However, the molecular mechanism of chemopreventive activity of green tea polyphenols is not fully understood. An abnormally elevated level of cyclooxygenase-2 (COX-2) is implicated in the pathogenesis of carcinogenesis. In the present study, we found that pretreatment of the green tea extract enriched with catechin and epigallocatechin gallate (EGCG) by gavage inhibited COX-2 expression induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin. Similarly, EGCG downregulated COX-2 in TPA-stimulated human mammary epithelial cells (MCF-10A) in culture. To further elucidate the underlying mechanism of COX-2 inhibition by green tea extract and EGCG, we examined their effects on the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), which are upstream enzymes known to regulate COX-2 expression in many cell types. Pretreatment with EGCG as well as green tea extract caused a decrease in the activation of ERK. In addition, EGCG inhibited the catalytic activity of ERK and p38 MAPK, suggesting that these signal-transducing enzymes could be potential targets for previously reported antitumor promoting activity of EGCG.
The aim of this study was to investigate the feasibility of the transdermal delivery of catechins and caffeine from green tea extract. Drug-in-adhesive patches containing 1.35, 1.03, 0.68, and 0.32 mg cm(-2) green tea extract were formulated and the dissolution of (-)-epigallocatechin gallate (EGCg), (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) from these was determined. Transdermal delivery was determined across full thickness pig ear skin from saturated solutions of green tea extract in pH 5.5 citrate-phosphate buffer, polyethylene glycol 400 and a 50:50 mixture of the citrate phosphate buffer and polyethylene glycol in addition to patches containing 1.35 mg cm(-2) green tea extract. Dissolution experiments indicated first order release which was dose dependent in respect of the loading level, although the amounts permeated were not always proportional to the amounts in the formulation. The highest percentage permeation of EGCg was found to be from the patch formulation. EGCg, EGC and EC were all successfully delivered transdermally from saturated solutions and adhesive patches containing green tea extract in this study. There was some evidence for the dermal metabolism of EGCg, but after 24 h 0.1% permeated from the patches containing 1.35 mg cm(-2) green tea extract. This was equivalent to the percentage absorbed after intragastric administration of green tea extract in rats. In addition, the concentration of EGCg in the Franz cell receptor chamber after 24 h permeation from the 0.9 cm diameter patch containing 1.35 mg cm(-2) was within the range of C-max plasma levels achieved after oral dosing of 2.2-4.2 g m(-2) green tea extract. Caffeine was also delivered at concentrations above those previously reported.
Green tea polyphenols have been shown to inhibit cancer in a variety of tumor models, including ultraviolet B (UVB)-induced non-melanoma skin cancer. In green tea extracts, the major dry mass constituent is the family of catechins, of which (-)-epigallocatechin-(3)-gallate (EGCG) is considered to be important for the chemopreventive activity. EGCG has been shown to have antioxidant properties, but there has been little progress toward identifying the specific targets and mechanisms of its action. Using cultured human keratinocytes, we show that UVB-induced AP-1 activity is inhibited by EGCG in a dose range of 5.45 nM to 54.5 μM. EGCG is effective at inhibiting AP-1 activity when applied before, after or both before and after UVB irradiation. EGCG also inhibits AP-1 activity in the epidermis of a transgenic mouse model. This work begins to define a mechanism by which EGCG could be acting to inhibit UVB-induced tumor formation.
(-)-Epigallocatechin gallate (EGCG) and theaflavins are believed to be the key active components in tea for the chemoprevention of cancer. However, the molecular mechanisms by which EGCG and theaflavins block carcinogenesis are not clear. In the JB6 mouse epidermal cell line a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which causes cell transformation at high frequency, markedly induced NF-κB activation. We found that EGCG and theaflavins inhibited TPA-induced NF-κB activity in a concentration-dependent manner. These polyphenols blocked TPA-induced phosphorylation of IκBα at Ser32 in the same concentration range. Moreover, the NF-κB sequence-specific DNA-binding activity induced by TPA was also inhibited by these polyphenols. These results suggest that inhibition of NF-κB activation is also important in accounting for the anti-tumor promotion effects of EGCG and theaflavins.
The effect of pretreatment of skin of Sencar mice with topically applied tannic acid, quercetin and green tea polyphenols (GTP) on the skin tumor initiating activity of (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-2) has been evaluated. The animals were pretreated with the plant phenols (tannic acid and quercetin (3000 nmol) or GTP 24 mg/mouse) for 7 days after which they received a single topical application of 200 nmol of BPDE-2 as the initiating agent. Beginning 7 days following initiation animals received twice weekly applications of 3.24 nmol of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Tannic acid and GTP afforded significant protection against skin tumor induction. These inhibitory effects were verified both by prolongation of the latency period and subsequent development of tumors. Quercetin, on the other hand, afforded only moderate protection. Each phenolic compound was found to be highly effective in accelerating the disappearance of BPDE-2 from aqueous medium. Our results suggest that tannic acid and GTP have substantial potential for protecting against the skin tumorigenic response to BPDE-2 and the mechanism of inhibition may involve inactivation of the reactive carcinogenic moiety.
Recent studies have shown that topical application of the tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA) to murine skin results in increased expression of the highly inflammatory cytokine interleukin (IL)-1α in the epidermis. This has led to the suggestion that IL-1α directly or indirectly mediates the inflammatory and hyperplastic responses elicited by TPA and possibly by other skin tumor promoters. In the current study, we investigated the effect of skin application of a polyphenolic fraction isolated from green tea (GTP) to SENCAR mice on skin tumor- promoter-caused induction of cutaneous edema and hyperplasia, and IL-1α mRNA expression. Pretreatment of the skin with GTP 30 mm before that of anthralin, benzoyl peroxide, mezerein, and TPA resulted in a significant (p < 0.05) inhibition of cutaneous edema and epidermal hyperplasia caused by each of these tumor promoters. Northern blot analysis indicated that topical application of TPA, anthralin, mezerein, or benzoyl peroxide to SENCAR mice resulted in an increased expression of epidermal IL-1α mRNA. Pretreatment of the skin with GTP or individual epicatechin derivatives (ECDs) present therein, 30 mm before that of TPA, resulted in a significant inhibition of enhanced expression of epidermal IL-1α mRNA caused by skin application of TPA. These inhibitory effects were found to be dependent on the dose of GTP. Among four epicatechin derivatives present in GTP, (-)-epicatechin-3-gallate and (-)-epigallocatechin-3-gallate were more effective than (-)-epigallocatechin and (-)-epicatechin in affording this inhibition. Preapplication of GTP was also found to afford inhibition against anthralin-, benzoyl peroxide-, and mezerein-caused increased expression of epidennal IL-1α mRNA and protein. Our study suggests that the inhibition of tumor-promoter-induced IL-1α mRNA and protein expression in mouse epidermis by green tea in combination with other inhibitory effects may be responsible for the anti-tumor-promoting and anti-inflammatory effects of GTP.
Based on our initial work with green tea, in which repeated topical applications of (−)-epigallocatechin gallate (EGCG), the main green tea polyphenol, inhibited tumor promotion in a two-stage carcinogenesis experiment on mouse skin (Phytother Res 1, 44–47, 1987), numerous scientists have since provided so much additional evidence of the benefits of drinking green tea that it is now an acknowledged cancer preventive in Japan, and will possibly soon be recognized as such in other countries. Our work has so far produced several important results with EGCG and green tea: a wide range of target organs in animal experiments for cancer prevention, wide bioavailability of 3H-EGCG in various organs of mice, delayed cancer onset of patients with a history of consuming over 10 cups of green tea per day, and absence of any severe adverse effects among volunteers who took 15 green tea tablets per day (2.25 g green tea extracts, 337.5 mg EGCG, and 135 mg caffeine) for 6 months. This paper introduces three new findings: 1) EGCG interacted with the phospholipid bilayer membrane resulting in confirmation of the sealing effect of EGCG; 2) EGCG inhibited TNF- gene expression in the cells and TNF- release from the cells; 3) high consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal Stage I and II breast cancer patients, and with increased expression of progesterone and estrogen receptors among postmenopausal ones. These results provide new insights into our understanding of the mechanisms of action of tea polyphenols and green tea extract as a cancer preventive.
Tea is the most popular beverage, consumed by over two thirds of the world's population. Tea is processed differently in different parts of the world to give green (20%), black (78%) or oolong tea (2%). Green tea is consumed mostly in Japan and China. The antimutagenic and anticarcinogenic activities of green tea are extensively examined. The chemical components of green and black tea are polyphenols, which include EC, ECG, EGC, EGCG and TFs. This article reviews the epidemiological and experimental studies on the antimutagenicity and anticarcinogenicity of tea extracts and tea polyphenols. In Japan, an epidemiological study showed an inverse relationship between habitual green tea drinking and the standardized mortality rates for cancer. Some cohort studies on Chanoyu (Japanese tea ceremony) women teachers also showed that their mortality ratio including deaths caused by malignant neoplasms were surprisingly low. The antimutagenic activity against various mutagens of tea extracts and polyphenols including ECG and EGCG has been demonstrated in microbial systems (Salmonella typhimurium and Escherichia coli), mammalian cell systems and in vivo animal tests. The anticarcinogenic activity of tea phenols has been shown in experimental animals such as rats and mice, in transplantable tumors, carcinogen-induced tumors in digestive organs, mammary glands, hepatocarcinomas, lung cancers, skin tumors, leukemia, tumor promotion and metastasis. The mechanisms of antimutagenesis and anticarcinogenesis of tea polyphenols suggest that the inhibition of tumors may be due to both extracellular and intracellular mechanisms including the modulation of metabolism, blocking or suppression, modulation of DNA replication and repair effects, promotion, inhibition of invasion and metastasis, and induction of novel mechanisms.