Photochemoprevention of cutaneous neoplasia through natural products
Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human tumors, representing 30% of the new cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the sun is a major cause of non-melanoma skin cancer in humans. The p...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2009
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| Цитувати: | Photochemoprevention of cutaneous neoplasia through natural products / A. Filip, S. Clichici, D. Daicoviciu, M. Adriana, I.D. Postescu, M. Perde-Schrepler, D. Olteanu // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 9-15. — Бібліогр.: 62 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
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irk-123456789-1349252018-06-15T03:03:41Z Photochemoprevention of cutaneous neoplasia through natural products Filip, A. Clichici, S. Daicoviciu, D. Adriana, M. Postescu, I.D. Perde-Schrepler, M. Olteanu, D. Reviews Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human tumors, representing 30% of the new cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the sun is a major cause of non-melanoma skin cancer in humans. The prevention and mainly the photochemoprevention with natural products represent a simple but very effective strategy in the management of cutaneous neoplasia. Here we review the progress in the research of new and existing agents developed to protect the skin exposed to UV. We also discuss the current state of knowledge on their photosuppression mechanism in humans as well as in animal models, and efficiency in cancer prevention 2009 Article Photochemoprevention of cutaneous neoplasia through natural products / A. Filip, S. Clichici, D. Daicoviciu, M. Adriana, I.D. Postescu, M. Perde-Schrepler, D. Olteanu // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 9-15. — Бібліогр.: 62 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/134925 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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English |
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Reviews Reviews |
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Reviews Reviews Filip, A. Clichici, S. Daicoviciu, D. Adriana, M. Postescu, I.D. Perde-Schrepler, M. Olteanu, D. Photochemoprevention of cutaneous neoplasia through natural products Experimental Oncology |
| description |
Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human tumors,
representing 30% of the new cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the sun is a major cause
of non-melanoma skin cancer in humans. The prevention and mainly the photochemoprevention with natural products represent
a simple but very effective strategy in the management of cutaneous neoplasia. Here we review the progress in the research of new
and existing agents developed to protect the skin exposed to UV. We also discuss the current state of knowledge on their photosuppression
mechanism in humans as well as in animal models, and efficiency in cancer prevention |
| format |
Article |
| author |
Filip, A. Clichici, S. Daicoviciu, D. Adriana, M. Postescu, I.D. Perde-Schrepler, M. Olteanu, D. |
| author_facet |
Filip, A. Clichici, S. Daicoviciu, D. Adriana, M. Postescu, I.D. Perde-Schrepler, M. Olteanu, D. |
| author_sort |
Filip, A. |
| title |
Photochemoprevention of cutaneous neoplasia through natural products |
| title_short |
Photochemoprevention of cutaneous neoplasia through natural products |
| title_full |
Photochemoprevention of cutaneous neoplasia through natural products |
| title_fullStr |
Photochemoprevention of cutaneous neoplasia through natural products |
| title_full_unstemmed |
Photochemoprevention of cutaneous neoplasia through natural products |
| title_sort |
photochemoprevention of cutaneous neoplasia through natural products |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2009 |
| topic_facet |
Reviews |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/134925 |
| citation_txt |
Photochemoprevention of cutaneous neoplasia through natural products / A. Filip, S. Clichici, D. Daicoviciu, M. Adriana, I.D. Postescu, M. Perde-Schrepler, D. Olteanu // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 9-15. — Бібліогр.: 62 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-09T22:24:21Z |
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2025-07-09T22:24:21Z |
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1837209865572843520 |
| fulltext |
Experimental Oncology 31, 9–15, 2009 (March) 9
Skin carcinomas represent 30% of the new cases of
malignancies diagnosed each year, and their incidence
is continually increasing. The main factor incriminated
in skin cancer is represented by the ultraviolet (UV)
radiation, especially type B (UVB) radiation, which
accounts for 90% of the skin cancer cases [1]. Each
year over 1.3 million cases of skin cancer are being
diagnosed in the United States [2]. The permanent
increase of the pre-malignant and malignant lesions,
the reduced efficiency of the photoprotective creams,
the uncontrolled exposure to sunlight are the reasons
of an increased interest in developing the new methods
of skin neoplasia prevention.
The chemoprevention using natural products
(polyphenols, monoterpene, flavonoids, indols, etc)
represents a new concept in attempts to control the
process of carcinogenesis: to prevent the development
of the tumors, to slow down their progression or even
to induce tumor regression [3, 4]. Some compounds
from fruits, vegetables and other plants prolong the
process of carcinogenesis [5]; they have anti-inflam-
matory, immunomodulatory and anti-oxidant property
[6], which is making them the ideal chemoprevention
agents of skin cancer.
This paper aims to review the main compounds
currently used for skin cancer chemoprevention.
Some of them are antioxidants (vitamin E, ascorbic
acid, polyphenols, isoflavonoids), which protect the
skin from the oxidative effects of UV radiation; others
interfere with the process of DNA repair or modulate
the immunosuppression induced by UV radiation [7].
To this day, there is no ideal compound that can provide
complete protection of the tissue against UV radiation.
Therefore, in vivo and in vitro studies are carried out to
identify the target molecules and signalling pathways
of different chemopreventive compounds, which would
increase their applicability in clinical practice.
THE ROLE OF ULTRAVIOLET RADIATION
IN CARCINOGENESIS
In 1894 Paul Gerson Unna established that there
is a direct causal relationship between exposure to
sunlight and the development of the cutaneous carci-
nomas. The UV radiation is a complete carcinogen be-
cause it initiates and promotes the tumor growth [4, 8].
In acute exposures it determines: erythema, oedema,
burns, pain, the thickening of the epidermis and skin
pigmentation [9], and after long and repeated expo-
sures it leads to immunosuppression [1], premature
ageing [10], and cutaneous carcinomas [11, 12].
The different wavelengths of UV radiation penetrate
the skin differently and, therefore, exert different bio-
logical effects. Although UVB radiation (290–320 nm)
represent 5% of the solar radiation, it is the most
dangerous, because it can induce burns and skin
cancers and can intervene in the initiation, promotion
and progression of tumor [1, 13, 14].
As a result of the interaction between the UV pho-
tons and the DNA molecules, the DNA is transformed
into excited state, in which the electrons are rear-
ranged and two photoproducts with a dipyrimidinic
structure are formed: the cyclobutane pyrimidine di-
mer (CPD) and 6-4 pyrimidine-pyrimidone (6-4PP) [7].
The development of these photoproducts interferes
with DNA-replication, preventing its repair and leading
to specific mutations. The most frequent mutations
of DNA after UVB irradiation include the substitution
PHOTOCHEMOPREVENTION OF CUTANEOUS NEOPLASIA
THROUGH NATURAL PRODUCTS
A. Filip1, *, S. Clichici1, D. Daicoviciu1, M. Adriana1, I.D. Postescu2, M. Perde-Schrepler2, D. Olteanu1
1Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca 400023,
Romania
2Oncologic Institute “Prof. Dr. I. Chiricuta”, Cluj-Napoca 400015, Romania
Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human tumors,
representing 30% of the new cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the sun is a major cause
of non-melanoma skin cancer in humans. The prevention and mainly the photochemoprevention with natural products represent
a simple but very effective strategy in the management of cutaneous neoplasia. Here we review the progress in the research of new
and existing agents developed to protect the skin exposed to UV. We also discuss the current state of knowledge on their photosup-
pression mechanism in humans as well as in animal models, and efficiency in cancer prevention.
Key Words: UV radiation, cancer, skin, chemoprotection, natural products.
Received: February 18, 2009.
*Correspondence: Fax: +40264597257
E-mail: adrianafilip33@yahoo.com
Abbreviations used: 6-4PP — 6-4 pyrimidine-pyrimidone; AP-1 —
activator protein-1; COX-2 — cyclooxygenase-2; CPD — cyclobu-
tane pyrimidine dimer; EC — epicatechin; ECG — epicatechin-3
gallate; EGC — epigallocatechin; EGCG — epigallocatchin-3
gallate; EGF — epidermal growth factor; ERK — extracellular
signal regulated kinase; IGF — insulin-like growth factor; iNOS —
inducible nitric oxide synthase; JNK — c-jun N-terminal kinase;
MAPK — mitogen activated protein kinases; MMPs — metallopro-
tease; NF-kB — nuclear factor-kappa B; p21 — cyclin-dependent
kinase inhibitor 1A; PCNA — proliferating cell nuclear antigen;
PUVA — photochemotherapy; STAT3 — signal transducer and acti-
vator of transcription 3; TNFα — tumor necrosis factor alpha; UV —
ultraviolet; VEGF — vascular endothelial growth factor.
Exp Oncol 2009
31, 1, 9–15
10 Experimental Oncology 31, 9–15, 2009 (March)
of cytosine base by thymine. It was noticed that the
methylation of the cytosine residues in the 5’-CCG and
5’-TCG sequences increased the formation of CPD
over 10 times, preferentially in p53 gene [15].
Usually the photoproducts formed after irradia-
tion are repaired effectively, but if the solar exposure
is chronic and excessive, the process of repair is
exceeded, the photoproducts persist and replicate,
which may lead to transcriptional errors and, finally,
to cancer [16]. The DNA lesions are repaired mainly
by nucleotide excision repair (NER) [16]. This process
is realised either by global genome repair (GGR),
involved in the repair of any sequence in the genome
regardless of its transcriptional status or by transcrip-
tion coupled repair (TCR), involved only in the repair
of actively transcribed DNA strands. The CPD repair is
not sufficient, because UVB radiation can determine
deletions and chromosomal aberrations [17].
Aside mutations, UV induces lipid peroxidation
reactions in the membrane of keratinocytes [18], de-
termines the oxidation of proteins, the isomerization
of the trans-urocanic acid, intensifies the activity of
metalloproteases (MMPs) in the dermis, determines
the breakage of the double-strand DNA resulting in
oxo-8-2’deoxyguanosine [19], and reduces the anti-
oxidant capacity of the skin [10].
The chemical carcinogenesis and that determined
by UVB is a complex process that takes place in well-
defined stages: initiation, promotion and progression.
The initiation stage is associated with the genotoxic
effect of the UV on the normal cells. The promotion
stage includes the clonal expansion of the cells that
were initiated and is considered reversible, as opposed
to the progression stage that needs other genotoxic
stimuli to transform the benign lesions, namely the
papillomas into carcinomas.
The mechanism by which UVB radiation induces
promotion is not yet well understood, but it is conside-
red that both the reactive oxygen species and also the
activation of the signalling cascades intervene in this
process, including the synthesis of prostaglandins,
which determines the clonal expansion of the initiated
cells [4, 20].
In the process of carcinogenesis, the immunosup-
pressive effect of the UV radiation has to be taken into
account. The UV radiation induces modifications of the
cellular mediated immunity: it decreases the numbers
of circulating T lymphocytes, the T helper/T suppres-
sors ratio decreases, the late onset hypersensitivity
reaction is modified [21]. Moreover, the native Langer-
hans’ cells in the skin are replaced by the population
of hystiocytes with a distinct antigenic profile and with
the capacity to stimulate the tumor suppressive T cells.
The chronic exposure to sun induces the occurrence
of inflammatory infiltrate, which is responsible for the
sunburn reaction. It correlates positively with the high
incidence of skin cancers and with premature ageing
of the skin [22]. When administered in drinking water
polyphenols from green tea noticeably reduce the
inflammatory response in animals [23]. The similar
effects were observed in humans [24]. For this reason,
the prevention of UV-induced immunosuppression
represents an important strategy in the management
of skin cancers [24].
CHEMOPREVENTION
The target of chemoprevention is interruption of
intracellular signals that transmit aberrant stimuli.
The use of natural compounds such as polyphenols,
monoterpene, flavonoids, organosulfides, indols as
chemopreventive agents showed promising results,
because they can influence on one or more stages of
carcinogenesis [3, 25].
To this day 30 classes of chemical compounds with
preventive effect were described, some of which are al-
ready used in clinics (Table 1). From these compounds,
a special attention was offered to polyphenols. They
proved their preventive effect in studies of different
carcinogens. This is very important because pollu-
tants, psychical stress, drugs, pesticides, UV radiation
induce the large quantities of free radicals, which play
an important role in the cancer development.
Polyphenols. In the last years the polyphenols
found in the green tea were the most studied com-
pounds because of their chemoprotective effect. More
than 765 papers, devoted to the preventive effect of
the green tea on tumors, were published [5]. There
are four classes of polyphenols that were isolated
from the Camellia Sinensis: epicatechin (EC), epica-
techin-3 gallate (ECG), epigallocatechin (EGC) and
epigallocatchin-3 gallate (EGCG). Among polyphenols
Table 1. Chemopreventive activity of plant-derived natural products in skin cancers
Plant Active principals Experimental model Mechanism of action
Curcuma longa Curcumin DMBA-TPA-induced mouse skin
papillomas
Suppression of extracellular signal regulated kinase activity
and NF-kB [26]
Curcumin DMBA-induced skin papillomas Antioxidant [27]
Ocimum sanctum Leaf extract DMBA-induced skin papillomagenesis in
Swiss albino mice
Antioxidant and detoxification mechanisms [28]
Ocimum
gratissimum
Clocimum oil DMBA-induced skin papillomas Antioxidant, elevation in hepatic and skin GST, sulfhydryl
(-SH), cytochrome b5 activity [29]
Vitis vinifera Proanthocyanidins
from grape seeds
DMBA-TPA-induced skin tumourigenesis
in mice
Suppression of ornithine decarboxylase, myeloperoxidase
and proteinkinase C [30]
Polyphenols from grape
seeds
DMBA-TPA-induced skin carcinogenesis Antioxidant [3]
Resveratrol from grape seeds skin cancer UV-induced in SKH-1
hairless mice
Inhibition of Survivin-phosphorylation and up-regulation of
Smac/DIABLO in skin tumors [1]
Withania
somnifera
Root extract DMBA-induced papillomas in mice Antioxidant [31]
Camellia sinensis Polyphenols from green tea UV irradiated SKH-1 hairless mice Antioxidant [35]
photocarcinogenesis in C3H/HeN mice Induce IL-12 and prevent immunosuppression UV-induced [57]
Experimental Oncology 31, 9–15, 2009 (March) 11
the most abandoned is EGCG (50–80%) [5]. Other
compounds were also identified, such as caffeine,
flavandiols, phenolic acids and alkaloids, such as
teobromin and teophilin.
Wang et al. [32] were the first who suggested that
polyphenols from green tea might have a protective
effect against the UV radiation. They showed that poly-
phenols administered superficially or in the drin king
water of SKH-1 mice prolonged the proliferation of ex-
perimental tumors in a dose-dependent manner [32].
They decreased the DNA damage [14] and reduced
the formation of CPD in the skin [33]. The green tea
and its polyphenols assured a good protection against
erythema, immunosuppression and photoageing of
the irradiated skin [34]. They reduced the number of
wrinkles and decreased the production of MMPs 2,
3, 7 and 9 [35]. EGCG inhibited the immunosuppres-
sion upon UV radiation and the production of reactive
oxygen species in the skin macrophages CD11b+ [23],
and increased the number of Langerhans’ cells.
Grapes are very rich in polyphenols, mainly the
seeds (60–70%) that contain the derivative of flavan-
3-ols called catechins. In contrast to polyphenols from
the green tea that are monomers, those from grapes
are dimers, trimers or oligomers, and are called pro-
cyanidins and proantocyanidins. Proantocyanidins
from grape seeds are more potent antioxidants and
scavengers for free radicals than the ascorbic acid or
vitamin E [24]. Using the different carcinogenesis mo-
dels, it was proved that they have an antitumor effect
[36], and reduce the rate of papillomas transformation
into carcinomas from 70% to 25% [24]. It was ob-
served that the polyphenols from grape seeds exhibit
antipromoter effect on tumors. This effect is of high
importance because in the process of carcinogenesis
the stage of tumor promotion is reversible, making it
an optimal stage for therapy application [36].
On a model of contact hypersensitivity induced in
mice by topical or systemic administration of 2,4-dinit-
rofluorobenzen it was observed that the proanthocya-
nidins have a protective effect on the immunosuppres-
sion induced by UVB. IL-12 and IL-10 are involved in
this process. They have an immunosuppressive effect;
their level is decreased decrease in the irradiated skin
and in the drainage lymphatic nodes after the adminis-
tration of proanthocyanides (should be edited) [24].
Trans-resveratrol (trans-3, 4′, 5-trihidroxistilbene)
is a chemoprotective agent found in red wine and
grape. It is responsible for the antitumor effect in dif-
ferent models of carcinogenesis [37]. Tested on SKH-1
mice, resveratrol exerts its effects by modulating the
function of survivin, a protein that inhibits apoptosis
[1]. The expression of survivin in tumors, especially
in melanoma, is associated with cellular proliferation
and angiogenesis [38], with an increase of tumor ag-
gressiveness and negative effect on patients’ survival
rate [1]. For this reason, the inhibition of survivin by
therapy is beneficial in advanced and recurrent cases
of malignancy and in acute UVB irradiation.
Ursolic acid. Ursolic acid is a triterpenoid pentacy-
clic compound isolated from flowers (Calluna vulgaris)
[39] or fruits (apples, plums), with an antiproliferative
and cytotoxic effect on different cell lines (multiple
mieloma, leukemia, osteosarcoma, mammary carci-
noma, lung, pancreatic and skin carcinoma etc) [40].
This compound mainly works by inducing the apop-
tosis of tumor cells.
The ursolic acid stimulates the activity of caspase-3
[41], reduces the activity of COX-2, interferes with en-
zymes that play a role in the DNA synthesis, it inhibits
the activity of lipooxygenasis, the activation of STAT3,
the activation of c-Src, Janus 1, Janus 2 kinases and
of the kinases regulated by extra-cellular signal (ERKs)
[42, 43]. Also, ursolic acid enhances the apoptotic ef-
fect of the antitumor agents used in therapy, and has
an anti-mutagen, anti-invasive and antiviral effect.
Some studies reveal the potent inhibitory effect
of this compound on epidermoid A431 carcinoma.
The ursolic acid reduces the tumor cells growth in
a dose-dependent manner by regulating the activity
of tyrosine kinase. The modulation of the signal path-
ways involved in carcinogenesis with the help of the
ursolic acid makes this product an attractive option for
chemoprevention/chemotherapy [44, 41].
Silibinin. Silibinin, a natural flavonoid used in the
whole world as a dietetic supplement due to its pho-
toprotective properties, was brought into view the
scientific world because of its protective effect in the
photoinduced lesions and in photocarcinogenesis.
These effects were discovered by topical and oral
administration of this compound [45]. Administering
as a part of the diet inhibits the DNA damage and/
or stimulates DNA repair, inhibits the proliferation of
epidermis cells by inducing the expression of p53
and p21/cip 1 in these cells. The p21 protein binds the
proliferating cell nuclear antigen (PCNA) and inhibits
its function in DNA replication. Superficial application
reduces the formation of thymine dimers immediately
after irradiation, not as much due to the sunscreen
effect as by interacting at a molecular level in the
epidermis [46].
Extract of Uncaria tomentosa. The watery extract
of Uncaria tomentosa (C-Med-100 or AC-11) increases
the reparation of the CPD formed after UVB irradiation.
This extract manifests its effect by the reparation of
excised bases and also by its antioxidant effect, which
leads to the reduction of 8-hydroxyguanine formation,
and also by the breakage of the DNA chains. After the
extract was administered through gavages to rats in
8 doses each of 40 mg/kg or 80 mg/kg of AC-11, after
the rats were irradiated with 12 Gy for 3 h, a complete
repair of the DNA strands was observed using both
doses [47]. The mechanism by which this compound
exerts its effect is still not well understood. It was
observed that Uncaria tomentosa extract reduces
the erythema and the formation of blisters post UV
exposure [21].
T4 endonucleases V. T4 endonuclease V (Dime-
ricine) is an enzyme recently synthetised in bacteria
12 Experimental Oncology 31, 9–15, 2009 (March)
and used in liposome with a protective purpose. It
manifests its effect by removing the DNA dimers,
especially the cyclobutane pyrimidine, restoring the
function of the p53 gene and by this exerting a pro-
tective effect over a long time period. It was used in
patients with xeroderma pigmentosum and in patients
after transplants to prevent the risk of cancer.
In a clinical trial, it was observed that T4 endonucle-
ase V reduced the incidence of basocellular cancer by
30% and of actinic keratosis by 68% [21]. Its effect on
actinic keratosis was noticed after 3 months of treat-
ment, suggesting that T4 endonuclease V compound
intervenes in the DNA repair process, influencing both
on the promotion and the progression of the tumor.
Upon superficial application, this compound is more
effective than the usual photoprotective products,
because it can be used after the UV irradiation and
even after sun burns [48].
The Polypodium leucotomos extract. The
Polypodium leucotomos extract derived from a plant
found in Central America is used in Spain as an oral
supplement in patients with arthritis and inflammatory
skin disorders (psoriasis) due to its anti-inflammatory
properties. It manifests its effect by scavenging the su-
peroxide anion, the singlet oxygen, the lipid peroxides
and hydroxyl radical. It offers protection after PUVA
therapy for vitiligo, it inhibits the formation of erythema
and of CPD, and it holds the Langerhans’ cells in the
skin [49]. The extract decreases the oxidative stress
and stimulate DNA repair.
CHEMOPREVENTION BY MODULATION
OF THE SIGNALLING PATHWAYS
The UV irradiation activates a few signalling
pathways, especially those involving the signalling
transmission from the nucleus to the plasma mem-
brane. These pathways are involved in photoageing,
in promoting the tumor growth and invasion, in the
survival and proliferation of the cells, and in different
DNA lesions. The polyphenols interfere with some
signal transduction pathways: p53, growth factors,
molecules that regulate the cellular cycle, such as
mitogen activated protein kinases (MAPKs), NF-kB,
AP-1, phosphatidylinositol 3-kinase and p70 S6-K.
Polyphenols and apoptosis, p53 and cell cycle
regulatory molecules. By apoptosis the unwanted
or damaged cells are eliminated from the system.
Thus, the induction of tumor cells apoptosis could be
considered as a protective mechanism against deve-
lopment and progression of cancer. Ahmad et al. [50]
performed the first studies regarding the role of EGCG
in the apoptosis of tumor cells in 1997. They observed
that EGCG protects the normal cells by reducing the
number of keratinocytes that were sunburned [14, 50].
Other scientific groups working on different cell lines
(skin, colon, lung, pancreas, and prostate) confirmed
these results [51]. EGCG stimulated apoptosis in pre-
cancer lesions (papillomas) and invasive squamous
carcinoma [52]. The differentiated effect of EGCG on
benign and malignant keratinocytes partially explains
its chemoprotective effect in photocarcinogenesis.
Although EGCG influences on more than one factor
associated with the progression of the cellular cycle, it
seems that the primary event is the inhibition of cycline
dependent kinases, thereby leading to the induction
of negative regulators.
To maintain the integrity of the healthy cells after
DNA damage, some cellular responses are activated
by transcriptional activation of p53, p21 and Bcl-2
family proteins: the scavenging of the damaged DNA,
a delay in the cellular cycle progression and DNA repair
[23]. The induction of p53 expression after the DNA
damage is associated with an increase in apoptosis
of the severely damaged cells. Some studies showed
that oral administration of green tea in nude SKH1 mice
increased the number of p53 and p21 positive cells
in epidermis after irradiation [5, 23]. In addition, the
expression of cycline D1 and the retinoblastoma pro-
tein phosphorylation were decreased. It was observed
that polyphenols induced nuclear condensation, the
activation of caspase 3 and the cleavage of poly (ADP)-
ribose polymerase. It determines the oligomerization
of Bax and the depolarization of the mitochondrial
membrane freeing the cytochrome c into the cytosol.
These findings are supported by the fact that adding
catalase to the cellular system prevents the apop-
tosis generated by EGCG [5]. Babli et al. [53] have
shown that treatment with different concentrations of
theaflavins and thearubigins from black tea on A375
cells resulted in reduction of Bcl-2 protein expression,
whereas increased the Bax expression. The increased
ratio of Bax/Bcl-2 proteins may be responsible for the
induction of apoptosis in these cells [53].
Polyphenols and MAPKs. MAPK family consist of
the extracellular signalling regulatory kinases (ERKs),
c-Jun N terminal kinases/stress-activated kinases
(JNKs/SAPKs) and p38MAPK proteins. MAPKs are
important regulators of the activator protein-1 (AP-1)
and nuclear NF-kB transcription factors [23]. The
treatment of normal human keratinocytes with EGCG
inhibits UV-induced phosphorylation of the MAPK
proteins through inhibiton of UV-mediated oxidative
stress [5]. The first observations regarding this effect
were made in studies in vitro on epidermis microsomes
from irradiated mice, which were pre-treated with poly-
phenols. Polyphenols were shown to inhibit the lipid
peroxidation and oxidation of proteins [23], inhibiting
the glutathione reduction and the decrease in anti-
oxidant enzymes (catalase and glutathion peroxidise)
activity [11]. It was shown that polyphenols reduce the
DNA damage mediated by the hydroxyl radicals by
a mechanism of transfer of electrons from the cate-
chin to the DNA radicals [54]. Applied on the skin of
volunteers before they were exposed to four minimum
erythema doses, polyphenols significantly reduced
the production of hydrogen peroxide and nitric oxide,
and also reduced the lipid peroxidation in dermis and
epidermis after UVB exposure [11].
Polyphenols and NF-kB. The UV radiation is
a potent stimulus for the NF-kB activation. NF- kB is
Experimental Oncology 31, 9–15, 2009 (March) 13
a transcription factor that belongs to the Rel family. It
regulates the expression of genes involved in inflam-
mation, immunity, cellular cycle progression, apop-
tosis and oncogenesis [55]. NF-kB is sequestered in
the cytoplasm in an inactive form due to the interac-
tion with IkB. When IkB is phosphorylated by the IkB
kinases (IKK), NF-kB is released and translocated to
the nucleus [56]. The activation of NF-kB increases
the expression of some pro-inflammatory cytokines
and COX-2 and iNOS [24]. Many of these genes are
over-expressed in cancers, including the cutaneous
ones, and the inhibition of NF-kB with proantocyani-
dines reduces their expression. EGCG more effectively
inhibited NF-kB activation mediated by TNFα on hu-
man epidermis carcinoma cells A431 than on normal
human keratinocytes [57]. Moreover, EGCG inhibited
the degradation and phosphorylation of IkBα, and
the activation UV-mediated of IKKα in normal human
keratinocytes in a time- and dose-dependent manner
[23, 56].
Polyphenols and AP-1. There is an increasing
amount of data that suggests the implication of the
transcription factor AP-1 in proliferation and survival
because of its ability to regulate the expression and
the function of some cellular cycle regulatory proteins,
such as cycline D1, p53, p21, p19 [23]. The treatment
of human keratinocytes HaKaT with EGCG inhibited the
UV-induced expression of c-fos, part of AP-1 heterodi-
mer [58]. Chen and Bowden [58] demonstrated that
the activation of p38MAPK and ERK is necessary for
UVB-induced c-fos expression in HaKaT cells.
Polyphenols, phosphatidylinositol-3-kinase/
Akt and p70 S6-K. Phosphatidylinositol-3-kinase
(PI3K) and its derived effector Akt/PKB have a crucial
role in protein synthesis, apoptosis, cellular growth and
mobility [23]. The UVB activates the epidermal growth
factor’s receptor, which initiates the phosphorylation
of Akt. Nomura et al. [59] demonstrated that EGCG
inhibits the activation of PI3K and UVB induced Akt
phosphorylation in mice’s epidermis cells, thus block-
ing the activation UVB-induced of p70 S6-K.
Polyphenols and the proteasome activation.
Some studies demonstrated that the proteasome 20S
is targeted by EGCG [5]. Proteasome 20S is respon-
sible for p53, p21, p27kip1, IkBα, and Bax degradation.
In vitro experiments showed that ECG and EGCG
inhibited the catalytic activity of the 20S complex and
intervened in the accumulation of p27kip1 and IkBα, and
by this induced cell cyle arrest in G1 phase [60].
Polyphenols and COX-2. It was found that cy-
clooxygenase-2 (COX-2) has an inadequate activity
in cancer. COX-2 is an enzyme, which expression is
induced by many factors: cytokines, growth factors
and tumor promoters. EGCG in concentration of
100 μmols/L inhibited the expression of mitogen-
stimulated COX-2 in the prostate androgen-sensitive
and androgen-insensitive tumor cells [61].
Polyphenols and the insulin-like growth factor.
Insulin-like growth factor (IGF) is an important growth
factor involved in maintaining of the normal functions
of the cell. The binding of free IGF and IGF-1 leads to
intramolecular auto-phosphorylation of the receptor
and to the phosphorylation of the specific targets. This
is followed by the activation of the PI3K/Akt and Ras/
MAPK signalling pathways. Polyphenols substantially
reduced the IGF-1 levels and increased the binding
protein-3 level in TRAMP mice [5].
Polyphenols and epidermal growth factor
receptor (EGFR). The epidermal growth factor
receptor (EGFR) is a membrane glycoprotein with
three domains: an extracellular, transmembrane and
intracellular with tyrosine kinase intrinsic activity. The
overexpression of EGFR induces a neoplasic cellular
phenotype. The administration of EGCG (10–20 μg/ml)
inhibits the activation of EGFR and other signalling
pathways in colon tumor cells [5]. EGCG binds to the
laminin receptor, expressed in many tumors, in this way
exerting its anti-cancer activity [62]. These findings
open the door for new studies, which will decipher the
mechanisms involved in cutaneous tumorigenesis.
Polyphenols and angiogenesis. Tumor growth
requires a continuous and supplementary supply of
nutrients and oxygen. To ensure these nutrients, the
tumors create new blood vessels. It was recently ob-
served that EGCG reduces the phosphorylation of the
VEGF receptor and induces apoptosis in chronic lym-
phocyte leukaemia [5]. Also, superficial application of
EGCG significantly inhibits UVB-induced tumor growth.
The inhibition of tumor growth was associated with the
reduction of the expression and activity of MMP-2 and
-9, which are the crucial factors in tumor invasion and
metastasis [36]. Studies demonstrated that EGCG
influences the activity of MMPs, both directly and
indirectly. The administration of polyphenols 0.1% in
the drinking water markedly inhibited the activi ty of
MMP-2 and -9 in the TRAMP mice with prostate can-
cer [5]. EGCG also inhibits the expression of VEGF in
photo-induced tumors and the expression of CD31 on
the surface of endothelial vascular cells [36].
CONCLUSIONS
UV radiation has multiple effects on the skin, inclu-
ding sunburn and premature aging, DNA mutations,
release of immunomodulatory cytokines, release of
reactive oxygen species and alteration of skin Langer-
hans’ cells. The combination of these events can lead
to the cancer development. The reviewed natural
products are potential candidates for the development
of chemopreventive and chemotherapeutic antitumor
agents. Understanding the molecular mechanisms
of their action and effects on cellular signaling pro-
cesses as well as their structure-activity relationships
is necessary for the generation of new more effective
derivatives.
ACKNOWLEDGMENTS
This work was financed by the Ministry of Educa-
tion, Research and Youth by 4 Program — Partnership
in priority fields (42104/2008).
14 Experimental Oncology 31, 9–15, 2009 (March)
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