Abstract
Ultraviolet (UV) radiation is one of the most abundant carcinogens in our environment,
and the development of non-melanoma skin cancers, the most common type of human malignancy
worldwide, represents one of the major consequences of excessive exposure. Because
of growing concerns that the level of UV radiation is increasing as a result of depletion
of the stratospheric ozone and climate change, the development of strategies for protection
of the skin is an urgent need. Many phytochemicals that belong to various families
of secondary metabolites, such as alkaloids (caffeine, sanguinarine), flavonoids [(−)-epigallocatechin
3-gallate, genistein, silibinin], carotenoids (β -carotene, lycopene), and isothiocyanates (sulforaphane), offer exciting platforms
for the development of such protective strategies. These phytochemicals have been
consumed by humans for many centuries as part of plant-rich diets and are presumed
to be of low toxicity, an essential requirement for a chemoprotective agent. Mechanistically,
they affect multiple signalling pathways and protect against UV radiation-inflicted
damage by their ability to act as direct and indirect antioxidants, as well as anti-inflammatory
and immunomodulatory agents. Such ”pluripotent character” is a critical prerequisite
for an agent that is designed to counteract the multiple damaging effects of UV radiation.
Especially attractive are inducers of the Keap1/Nrf2/ARE pathway, which controls the
gene expression of proteins whose activation leads to enhanced protection against
oxidants and electrophiles. Such protection is comprehensive, long-lasting, and unlikely
to cause pro-oxidant effects or interfere with the synthesis of vitamin D.
Abbreviations
AP-1:activator protein 1
ARE:antioxidant response element
COX-2:cyclooxygenase 2
EGG:epigallocatechin 3-gallate
EGF:epidermal growth factor
GSH:glutathione
iNOS:inducible nitric oxide synthase
Keap1:Kelch-like ECH-associated protein 1
IL:inerleukin
MAPK:mitogen-activated protein kinase
MMP:matrix metalloprotease
NF-κB:nuclear factor-κB
NQO1:NAD(P)H:quinone oxidoreductase 1
Nrf2:nuclear factor-erythroid 2-related factor 2
ODC:ornithine decarobxylase
PCNA:proliferating cell nuclear antigen
ROS:reactive oxygen species
TPA:12-O -tetradecanoylphorbol 13-acetate
UV:ultraviolet
Key words
caffeine - epigallocatechin 3-gallate - lycopene - silibinin - skin cancer - sulforaphane
References
1
Diffey B.
Climate change, ozone depletion and the impact on ultraviolet exposure of human skin.
Phys Med Biol.
2004;
49
R1-11
2
de Gruijl F R, Longstreth J, Norval M, Cullen A P, Slaper H, Kripke M L. et al .
Health effects from stratospheric ozone depletion and interactions with climate change.
Photochem Photobiol Sci.
2003;
2
16-28
3
Norval M, Cullen A P, de Gruijl F R, Longstreth J, Takizawa Y, Lucas R M. et al .
The effects on human health from stratospheric ozone depletion and its interactions
with climate change.
Photochem Photobiol Sci.
2007;
6
232-51
4
Diffey B L.
Solar ultraviolet radiation effects on biological systems.
Phys Med Biol.
1991;
36
299-328
5
Diffey B L.
What is light.
Photodermatol Photoimmunol Photomed.
2002;
18
68-74
6
Sies H, Stahl W.
Carotenoids and UV protection.
Photochem Photobiol Sci.
2004;
3
749-52
7
Karran P, Attard N.
Thiopurines in current medical practice: molecular mechanisms and contributions to
therapy-related cancer.
Nat Rev Cancer.
2008;
8
24-36
8
Mitchell D.
Revisiting the photochemistry of solar UVA in human skin.
Proc Natl Acad Sci USA.
2006;
103
13 567-8
9
Godar D E.
UV doses worldwide.
Photochem Photobiol.
2005;
81
736-49
10
Young R W.
The family of sunlight-related eye diseases.
Optom Vis Sci.
1994;
71
125-44
11
Alam M, Ratner D.
Cutaneous squamous-cell carcinoma.
N Engl J Med.
2001;
344
975-83
12
Diepgen T L, Mahler V.
The epidemiology of skin cancer.
Br J Dermatol.
2002;
146 (Suppl 61)
1-6
13 NIH publication No. 95 – 1564 1995
14
van Steeg H, Kraemer K H.
Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer.
Mol Med Today.
1999;
5
86-94
15
Setlow R B, Carrier W L.
Pyrimidine dimers in ultraviolet-irradiated DNA′s.
J Mol Biol.
1966;
17
237-54
16
Cadet J, Sage E, Douki T.
Ultraviolet radiation-mediated damage to cellular DNA.
Mutat Res.
2005;
571
3-17
17
Daya-Grosjean L, Sarasin A.
UV-specific mutations of the human patched gene in basal cell carcinomas from normal
individuals and xeroderma pigmentosum patients.
Mutat Res.
2000;
450
93-9
18
Daya-Grosjean L, Dumaz N, Sarasin A.
The specificity of p53 mutation spectra in sunlight induced human cancers.
J Photochem Photobiol B.
1995;
28
115-24
19
Daya-Grosjean L, Robert C, Drougard C, Suarez H, Sarasin A.
High mutation frequency in ras genes of skin tumors isolated from DNA repair deficient
xeroderma pigmentosum patients.
Cancer Res.
1993;
53
1625-9
20
Ziegler A, Jonason A S, Leffell D J, Simon J A, Sharma H W, Kimmelman J. et al .
Sunburn and p53 in the onset of skin cancer.
Nature.
1994;
372
773-6
21
Williams C, Pontén F, Ahmadian A, Ren Z P, Ling G, Rollman O. et al .
Clones of normal keratinocytes and a variety of simultaneously present epidermal neoplastic
lesions contain a multitude of p53 gene mutations in a xeroderma pigmentosum patient.
Cancer Res.
1998;
58
2449-55
22
Au V, Madison S A.
Effects of singlet oxygen on the extracellular matrix protein collagen: oxidation
of the collagen crosslink histidinohydroxylysinonorleucine and histidine.
Arch Biochem Biophys.
2000;
384
133-42
23
Mouret S, Baudouin C, Charveron M, Favier A, Cadet J, Douki T.
Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed
to UVA radiation.
Proc Natl Acad Sci USA.
2006;
103
13 765-70
24
Nijhof J G, van Pelt C, Mulder A A, Mitchell D L, Mullenders L H, de Gruijl F R.
Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite
NER proficiency.
Carcinogenesis.
2007;
28
792-800
25
Nijhof J G, Mulder A M, Speksnijder E N, Hoogervorst E M, Mullenders L H, de Gruijl F R.
Growth stimulation of UV-induced DNA damage retaining epidermal basal cells gives
rise to clusters of p53 overexpressing cells.
DNA Repair (Amst).
2007;
6
1642-50
26
Melnikova V O, Ananthaswamy H N.
Cellular and molecular events leading to the development of skin cancer.
Mutat Res.
2005;
571
91-106
27
Klotz L O, Pellieux C, Briviba K, Pierlot C, Aubry J M, Sies H.
Mitogen-activated protein kinase (p38-, JNK-, ERK-) activation pattern induced by
extracellular and intracellular singlet oxygen and UVA.
Eur J Biochem.
1999;
260
917-22
28
Silvers A L, Bachelor M A, Bowden G T.
The role of JNK and p38 MAPK activities in UVA-induced signaling pathways leading
to AP-1 activation and c-Fos expression.
Neoplasia.
2003;
5
319-29
29
Bachelor M A, Bowden G T.
UVA-mediated activation of signaling pathways involved in skin tumor promotion and
progression.
Semin Cancer Biol.
2004;
14
131-8
30
Cooper S J, Bowden G T.
Ultraviolet B regulation of transcription factor families: roles of nuclear factor-kappa
B (NF-κB) and activator protein-1 (AP-1) in UVB-induced skin carcinogenesis.
Curr Cancer Drug Targets.
2007;
7
325-34
31
Kripke M L.
Immunological unresponsiveness induced by ultraviolet radiation.
Immunol Rev.
1984;
80
87-102
32
Halliday G M.
Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced
oxidative damage contributes to photocarcinogenesis.
Mutat Res.
2005;
571
107-20
33
Simon J C, Krutmann J, Elmets C A, Bergstresser P R, Cruz J r.
PD. Ultraviolet B-irradiated antigen-presenting cells display altered accessory signaling
for T-cell activation: relevance to immune responses initiated in skin.
J Invest Dermatol.
1992;
98
66S-9S
34
Vermeer M, Streilein J W.
Ultraviolet B light-induced alterations in epidermal Langerhans cells are mediated
in part by tumor necrosis factor-alpha.
Photodermatol Photoimmunol Photomed.
1990;
7
258-65
35
Chung H T, Burnham D K, Robertson B, Roberts L K, Daynes R A.
Involvement of prostaglandins in the immune alterations caused by the exposure of
mice to ultraviolet radiation.
J Immunol.
1986;
137
2478-84
36
Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer H D.
The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by
keratinocytes.
Curr Biol.
2007;
17
1140-5
37
Schwarz T, Luger T A.
Effect of UV irradiation on epidermal cell cytokine production.
J Photochem Photobiol B.
1989;
4
1-13
38
Chung J H, Youn S H, Koh W S, Eun H C, Cho K H, Park K C. et al .
Ultraviolet B irradiation-enhanced interleukin (IL)-6 production and mRNA expression
are mediated by IL-1α in cultured human keratinocytes.
J Invest Dermatol.
1996;
106
715-20
39
Yano S, Banno T, Walsh R, Blumenberg M.
Transcriptional responses of human epidermal keratinocytes to cytokine interleukin-1.
J Cell Physiol.
2008;
214
1-13
40
Kondo S, Kono T, Sauder D N, McKenzie R C.
IL-8 gene expression and production in human keratinocytes and their modulation by
UVB.
J Invest Dermatol.
1993;
101
690-4
41
Schwarz A, Schwarz T.
Molecular determinants of UV-induced immunosuppression.
Exp Dermatol.
2002;
11 (Suppl 1)
9-12
42
Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T. et al .
IL-10 controls ultraviolet-induced carcinogenesis in mice.
J Immunol.
2007;
179
365-71
43
Schwarz A, Grabbe S, Aragane Y, Sandkuhl K, Riemann H, Luger T A. et al .
Interleukin-12 prevents ultraviolet B-induced local immunosuppression and overcomes
UVB-induced tolerance.
J Invest Dermatol.
1996;
106
1187-91
44
Riemann H, Schwarz A, Grabbe S, Aragane Y, Luger T A, Wysocka M. et al .
Neutralization of IL-12 in vivo prevents induction of contact hypersensitivity and
induces hapten-specific tolerance.
J Immunol.
1996;
156
1799-803
45
Schwarz A, Ständer S, Berneburg M, Böhm M, Kulms D, van Steeg H. et al .
Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA
repair.
Nat Cell Biol.
2002;
4
26-31
46
Maeda A, Schneider S W, Kojima M, Beissert S, Schwarz T, Schwarz A.
Enhanced photocarcinogenesis in interleukin-12-deficient mice.
Cancer Res.
2006;
66
2962-9
47
Andersen P H, Abrams K, Bjerring P, Maibach H.
A time-correlation study of ultraviolet B-induced erythema measured by reflectance
spectroscopy and laser Doppler flowmetry.
Photodermatol Photoimmunol Photomed.
1991;
8
123-8
48
Andersen P H, Abrams K, Maibach H.
Ultraviolet B dose-dependent inflammation in humans: a reflectance spectroscopic and
laser Doppler flowmetric study using topical pharmacologic antagonists on irradiated
skin.
Photodermatol Photoimmunol Photomed.
1992;
9
17-23
49
Andersen P H, Bjerring P.
Spectral reflectance of human skin in vivo.
Photodermatol Photoimmunol Photomed.
1990;
7
5-12
50
Wagner J K, Jovel C, Norton H L, Parra E J, Shriver M D.
Comparing quantitative measures of erythema, pigmentation and skin response using
reflectometry.
Pigment Cell Res.
2002;
15
379-84
51
O’Donovan P, Perrett C M, Zhang X, Montaner B, Xu Y Z, Harwood C A. et al .
Azathioprine and UVA light generate mutagenic oxidative DNA damage.
Science.
2005;
309
1871-4
52
Young A R, Sheehan J M, Chadwick C A, Potten C S.
Protection by ultraviolet A and B sunscreens against in situ dipyrimidine photolesions
in human epidermis is comparable to protection against sunburn.
J Invest Dermatol.
2000;
115
37-41
53
Fitzpatrick T B.
The validity and practicality of sun-reactive skin types I through VI.
Arch Dermatol.
1988;
124
869-71
54
Sies H, Stahl W.
Nutritional protection against skin damage from sunlight.
Annu Rev Nutr.
2004;
24
173-200
55 Ziegler J, Facchini P J. Alkaloid biosynthesis: metabolism and trafficking. Annu
Rev Plant Biol, in press
56
Zajdela F, Latarjet R.
Effect inhibiteurs de caffeine sur l’induction de cancers par les rayons ultraviolet
chex la souris.
C R Acad Sci Hebd Seances Acad Sci D..
1973;
277
1073-6
57
Zajdela F, Latarjet R.
Inhibition of skin carcinogenesis in vivo by caffeine and other agents.
Natl Cancer Inst Monogr.
1978;
50
33-40
58
Bowden G T, Giesselbach B, Fusenig N E.
Postreplication repair of DNA in ultraviolet light-irradiated normal and malignancy
transformed mouse epidermal cell cultures.
Cancer Res.
1978;
38
2709-18
59
Bowden G T, Fusenig N E.
Caffeine inhibition of postreplication repair of UV-damaged DNA in mouse cells.
Chem Biol Interact.
1980;
33
101-13
60
Lou Y R, Lu Y P, Xie J G, Huang M T, Conney A H.
Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation
and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B
light.
Nutr Cancer.
1999;
33
146-53
61
Lu Y P, Lou Y R, Liao J, Xie J G, Peng Q Y, Yang C S. et al .
Administration of green tea or caffeine enhances the disappearance of UVB-induced
patches of mutant p53 positive epidermal cells in SKH-1 mice.
Carcinogenesis.
2005;
26
1465-72
62
Lu Y P, Lou Y R, Lin Y, Shih W J, Huang M T, Yang C S. et al .
Inhibitory effects of orally administered green tea, black tea, and caffeine on skin
carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice):
relationship to decreased tissue fat.
Cancer Res.
2001;
61
5002-9
63
Lu Y P, Lou Y R, Peng Q Y, Xie J G, Nghiem P, Conney A H.
Effect of caffeine on the ATR/Chk1 pathway in the epidermis of UVB-irradiated mice.
Cancer Res.
2008;
68
2523-9
64
Lu Y P, Lou Y R, Nolan B, Peng Q Y, Xie J G, Wagner G C. et al .
Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis
in the skin of UVB light-irradiated mice.
Proc Natl Acad Sci USA.
2006;
103
16 301-6
65
Lu Y P, Nolan B, Lou Y R, Peng Q Y, Wagner G C, Conney A H.
Voluntary exercise together with oral caffeine markedly stimulates UVB light-induced
apoptosis and decreases tissue fat in SKH-1 mice.
Proc Natl Acad Sci USA.
2007;
104
12 936-41
66
Lu Y P, Lou Y R, Xie J G, Peng Q Y, Liao J, Yang C S. et al .
Topical applications of caffeine or (–)-epigallocatechin gallate (EGCG) inhibit carcinogenesis
and selectively increase apoptosis in UVB-induced skin tumors in mice.
Proc Natl Acad Sci USA.
2002;
99
12 455-60
67
Conney A H, Kramata P, Lou Y R, Lu Y P.
Effect of caffeine on UVB-induced carcinogenesis, apoptosis, and the elimination of
UVB-induced patches of p53 mutant epidermal cells in SKH-1 mice.
Photochem Photobiol.
2008;
84
330-8
68
Koo S W, Hirakawa S, Fujii S, Kawasumi M, Nghiem P.
Protection from photodamage by topical application of caffeine after ultraviolet irradiation.
Br J Dermatol.
2007;
156
957-64
69
Lu Y P, Lou Y R, Xie J G, Peng Q Y, Zhou S, Lin Y. et al .
Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced
apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice.
Carcinogenesis.
2007;
28
199-206
70
Conney A H, Zhou S, Lee M J, Xie J G, Yang C S, Lou Y R. et al .
Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced
apoptosis in the epidermis of SKH-1 mice.
Toxicol Appl Pharmacol.
2007;
224
209-13
71 Rogozin E A, Lee K W, Kang N J, Yu H, Nomura M, Miyamoto K I. et al .Inhibitory
effects of caffeine analogues on neoplastic transformation: structure-activity relationship. Carcinogenesis,
in press
72
Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C. et al .
Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers.
Int J Cancer.
2006;
118
103-7
73
Kurozawa Y, Ogimoto I, Shibata A, Nose T, Yoshimura T, Suzuki H. et al .
Coffee and risk of death from hepatocellular carcinoma in a large cohort study in
Japan.
Br J Cancer.
2005;
93
607-10
74
Gelatti U, Covolo L, Franceschini M, Pirali F, Tagger A, Ribero M L. et al .
Coffee consumption reduces the risk of hepatocellular carcinoma independently of its
aetiology: a case-control study.
J Hepatol.
2005;
42
528-34
75
Baker J A, McCann S E, Reid M E, Nowell S, Beehler G P, Moysich K B.
Associations between black tea and coffee consumption and risk of lung cancer among
current and former smokers.
Nutr Cancer.
2005;
52
15-21
76
Hakim I A, Harris R B, Weisgerber U M.
Tea intake and squamous cell carcinoma of the skin: influence of type of tea beverages.
Cancer Epidemiol Biomarkers Prev.
2000;
9
727-31
77
Rees J R, Stukel T A, Perry A E, Zens M S, Spencer S K, Karagas M R.
Tea consumption and basal cell and squamous cell skin cancer: results of a case-control
study.
J Am Acad Dermatol.
2007;
56
781-5
78
Abel E L, Hendrix S O, McNeeley S G, Johnson K C, Rosenberg C A, Mossavar-Rahmani Y.
et al .
Daily coffee consumption and prevalence of nonmelanoma skin cancer in Caucasian women.
Eur J Cancer Prev.
2007;
16
446-52
79
Mitscher L A, Park Y H, Clark D, Clark III G W, Hammesfahr P D, Wu W N. et al .
Antimicrobial agents from higher plants. An investigation of Hunnemannia fumariaefolia
pseudoalcoholates of sanguinarine and chelerythrine.
Lloydia.
1978;
41
145-50
80
Lenfeld J, Kroutil M, Marsálek E, Slavík J, Preininger V, Simánek V.
Antiinflammatory activity of quaternary benzophenanthridine alkaloids from Chelidonium
majus.
Planta Med.
1981;
43
161-5
81
Reagan-Shaw S, Breur J, Ahmad N.
Enhancement of UVB radiation-mediated apoptosis by sanguinarine in HaCaT human immortalized
keratinocytes.
Mol Cancer Ther.
2006;
5
418-29
82
Ahsan H, Reagan-Shaw S, Eggert D M, Tan T C, Afaq F, Mukhtar H. et al .
Protective effect of sanguinarine on ultraviolet B-mediated damages in SKH-1 hairless
mouse skin: implications for prevention of skin cancer.
Photochem Photobiol.
2007;
83
986-93
83
Ross J A, Kasum C M.
Dietary flavonoids: bioavailability, metabolic effects, and safety.
Annu Rev Nutr.
2002;
22
19-34
84
Dinkova-Kostova A T.
Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic
enzymes.
Mini Rev Med Chem.
2002;
2
595-610
85 Dinkova-Kostova A T, Talalay P. Direct and indirect antioxidant properties of inducers
of cytoprotective proteins. Mol Nutr Food Res, in press
86
Williams R J, Spencer J P, Rice-Evans C.
Flavonoids: antioxidants or signalling molecules?.
Free Radic Biol Med.
2004;
36
838-49
87
Richelle M, Sabatier M, Steiling H, Williamson G.
Skin bioavailability of dietary vitamin E, carotenoids, polyphenols, vitamin C, zinc
and selenium.
Br J Nutr.
2006;
96
227-38
88
Barthelman M, Bair III W B, Stickland K K, Chen W, Timmermann B N, Valcic S. et al
.
(–)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1 activity.
Carcinogenesis.
1998;
19
2201-4
89
Chen W, Dong Z, Valcic S, Timmermann B N, Bowden G T.
Inhibition of ultraviolet B--induced c-fos gene expression and p38 mitogen-activated
protein kinase activation by (–)-epigallocatechin gallate in a human keratinocyte
cell line.
Mol Carcinogen.
1999;
24
79-84
90
Mittal A, Piyathilake C, Hara Y, Katiyar S K.
Exceptionally high protection of photocarcinogenesis by topical application of (–)-epigallocatechin-3-gallate
in hydrophilic cream in SKH-1 hairless mouse model: relationship to inhibition of
UVB-induced global DNA hypomethylation.
Neoplasia.
2003;
5
555-65
91
Mantena S K, Roy A M, Katiyar S K.
Epigallocatechin-3-gallate inhibits photocarcinogenesis through inhibition of angiogenic
factors and activation of CD8+ T cells in tumors.
Photochem Photobiol.
2005;
81
1174-9
92
Katiyar S K, Challa A, McCormick T S, Cooper K D, Mukhtar H.
Prevention of UVB-induced immunosuppression in mice by the green tea polyphenol (–)-epigallocatechin-3-gallate
may be associated with alterations in IL-10 and IL-12 production.
Carcinogenesis.
1999;
20
2117-24
93
Katiyar S K, Matsui M S, Elmets C A, Mukhtar H.
Polyphenolic antioxidant (–)-epigallocatechin-3-gallate from green tea reduces UVB-induced
inflammatory responses and infiltration of leukocytes in human skin.
Photochem Photobiol.
1999;
69
148-53
94
Katiyar S, Elmets C A, Katiyar S K.
Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair.
J Nutr Biochem.
2007;
18
287-96
95
Katiyar S K, Mukhtar H.
Green tea polyphenol (–)-epigallocatechin-3-gallate treatment to mouse skin prevents
UVB-induced infiltration of leukocytes, depletion of antigen-presenting cells, and
oxidative stress.
J Leukoc Biol.
2001;
69
719-26
96
Meeran S M, Mantena S K, Katiyar S K.
Prevention of ultraviolet radiation-induced immunosuppression by (–)-epigallocatechin-3-gallate
in mice is mediated through interleukin 12-dependent DNA repair.
Clin Cancer Res.
2006;
12
2272-80
97
Meeran S M, Mantena S K, Elmets C A, Katiyar S K.
(–)-Epigallocatechin-3-gallate prevents photocarcinogenesis in mice through interleukin-12-dependent
DNA repair.
Cancer Res.
2006;
66
5512-20
98
Schwarz A, Maeda A, Gan D, Mammone T, Matsui M S, Schwarz T.
Green tea phenol extracts reduce UVB-induced DNA damage in human cells via Interleukin-12.
Photochem Photobiol.
2008;
84
350-5
99
Katiyar S K, Afaq F, Perez A, Mukhtar H.
Green tea polyphenol (–)-epigallocatechin-3-gallate treatment of human skin inhibits
ultraviolet radiation-induced oxidative stress.
Carcinogenesis.
2001;
22
287-94
100
Lee M J, Maliakal P, Chen L, Meng X, Bondoc F Y, Prabhu S. et al .
Pharmacokinetics of tea catechins after ingestion of green tea and (–)-epigallocatechin-3-gallate
by humans: formation of different metabolites and individual variability.
Cancer Epidemiol Biomarkers Prev.
2002;
11
025-32
101
Chow H H, Cai Y, Hakim I A, Crowell J A, Shahi F, Brooks C A. et al .
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration
of epigallocatechin gallate and polyphenon E in healthy individuals.
Clin Cancer Res.
2003;
9
3312-9
102
Heinrich U, Neukam K, Tronnier H, Sies H, Stahl W.
Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced
erythema and improves skin condition in women.
J Nutr.
2006;
136
1565-9
103
Wei H, Saladi R, Lu Y, Wang Y, Palep S R, Moore J. et al .
Isoflavone genistein: photoprotection and clinical implications in dermatology.
J Nutr.
2003;
133
3811S-9S
104
Isoherranen K, Punnonen K, Jansen C, Uotila P.
Ultraviolet irradiation induces cyclooxygenase-2 expression in keratinocytes.
Br J Dermatol.
1999;
140
1017-22
105
Miller C C, Hale P, Pentland A P.
Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent
pathway. Evidence for UVB-induced epidermal growth factor receptor activation.
J Biol Chem.
1994;
269
3529-33
106
Isoherranen K, Westermarck J, Kähäri V M, Jansén C, Punnonen K.
Differential regulation of the AP-1 family members by UV irradiation in vitro and
in vivo.
Cell Signal.
1998;
10
191-5
107
Mazière C, Dantin F, Dubois F, Santus R, Mazière J.
Biphasic effect of UVA radiation on STAT1 activity and tyrosine phosphorylation in
cultured human keratinocytes.
Free Radic Biol Med.
2000;
28
1430-7
108
Widyarini S, Spinks N, Husband A J, Reeve V E.
Isoflavonoid compounds from red clover (Trifolium pratense) protect from inflammation
and immune suppression induced by UV radiation.
Photochem Photobiol.
2001;
74
465-70
109
Brand R M, Jendrzejewski J L.
Topical treatment with (–)-epigallocatechin-3-gallate and genistein after a single
UV exposure can reduce skin damage.
J Dermatol Sci.
2008;
50
69-72
110
Moore J O, Wang Y, Stebbins W G, Gao D, Zhou X, Phelps R. et al .
Photoprotective effect of isoflavone genistein on ultraviolet B-induced pyrimidine
dimer formation and PCNA expression in human reconstituted skin and its implications
in dermatology and prevention of cutaneous carcinogenesis.
Carcinogenesis.
2006;
27
1627-35
111
Rohdewald P.
A review of the French maritime pine bark extract (Pycnogenol), a herbal medication
with a diverse clinical pharmacology.
Int J Clin Pharmacol Ther.
2002;
40
158-68
112
Cho K J, Yun C H, Yoon D Y, Cho Y S, Rimbach G, Packer L. et al .
Effect of bioflavonoids extracted from the bark of Pinus maritima on proinflammatory
cytokine interleukin-1 production in lipopolysaccharide-stimulated RAW 264.7.
Toxicol Appl Pharmacol.
2000;
168
64-71
113
Cho K J, Yun C H, Packer L, Chung A S.
Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritima on
the expression of proinflammatory cytokines.
Ann N Y Acad Sci.
2001;
928
141-56
114
Packer L, Rimbach G, Virgili F.
Antioxidant activity and biologic properties of a procyanidin-rich extract from pine
(Pinus maritima) bark, pycnogenol.
Free Radic Biol Med.
1999;
27
704-24
115
Sime S, Reeve V E.
Protection from inflammation, immunosuppression and carcinogenesis induced by UV radiation
in mice by topical Pycnogenol.
Photochem Photobiol.
2004;
79
193-8
116
Singh R P, Agarwal R.
Mechanisms and preclinical efficacy of silibinin in preventing skin cancer.
Eur J Cancer.
2005;
41
1969-79
117
Meeran S M, Katiyar S, Elmets C A, Katiyar S K.
Silymarin inhibits UV radiation-induced immunosuppression through augmentation of
interleukin-12 in mice.
Mol Cancer Ther.
2006;
5
1660-8
118
Gu M, Singh R P, Dhanalakshmi S, Agarwal C, Agarwal R.
Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in
SKH-1 hairless mice.
Cancer Res.
2007;
67
3483-91
119
El-Agamey A, Lowe G M, McGarvey D J, Mortensen A, Phillip D M, Truscott T G. et al
.
Carotenoid radical chemistry and antioxidant/pro-oxidant properties.
Arch Biochem Biophys.
2004;
430
37-48
120
Demmig-Adams B, Gilmore A M, Adams III W W.
Carotenoids 3: in vivo function of carotenoids in higher plants.
FASEB J.
1996;
10
403-12
121
Demmig-Adams B, Adams III W W.
Antioxidants in photosynthesis and human nutrition.
Science.
2002;
298
2149-53
122
Stahl W, Sies H.
Carotenoids and flavonoids contribute to nutritional protection against skin damage
from sunlight.
Mol Biotechnol.
2007;
37
26-30
123
Stahl W, Heinrich U, Aust O, Tronnier H, Sies H.
Lycopene-rich products and dietary photoprotection.
Photochem Photobiol Sci.
2006;
5
238-42
124
Stahl W, Heinrich U, Wiseman S, Eichler O, Sies H, Tronnier H.
Dietary tomato paste protects against ultraviolet light-induced erythema in humans.
J Nutr.
2001;
131
1449-51
125
Heinrich U, Gärtner C, Wiebusch M, Eichler O, Sies H, Tronnier H. et al .
Supplementation with beta-carotene or a similar amount of mixed carotenoids protects
humans from UV-induced erythema.
J Nutr.
2003;
133
98-101
126
Fahey J W, Stephenson K K, Dinkova-Kostova A T, Egner P A, Kensler T W, Talalay P.
Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian
phase 2 cytoprotective genes.
Carcinogenesis.
2005;
26
1247-55
127 Khachik F, Bertram J S, Huang M -T, Fahey J W, Talalay P. Dietary carotenoids
and their metabolites as potentially useful chemoprotective agents against cancer. In:
Packer L, Hiramatsu M, Yoshikawa T, editors
Proceedings of the International Symposium on Antioxidant Food Supplements in Human
Health . Oxford; Academic Press 1999: 203-29
128
Fahey J W, Zalcmann A T, Talalay P.
The chemical diversity and distribution of glucosinolates and isothiocyanates among
plants.
Phytochemistry.
2001;
56
5-51
129
Wittstock U, Halkier B A.
Glucosinolate research in the Arabidopsis era.
Trends Plant Sci.
2002;
7
263-70
130
Halkier B A, Gershenzon J.
Biology and biochemistry of glucosinolates.
Annu Rev Plant Biol.
2006;
57
303-33
131
Wittstock U, Gershenzon J.
Constitutive plant toxins and their role in defense against herbivores and pathogens.
Curr Opin Plant Biol.
2002;
5
300-7
132
Matusheski N V, Juvik J A, Jeffery E H.
Heating decreases epithiospecifier protein activity and increases sulforaphane formation
in broccoli.
Phytochemistry.
2004;
65
1273-81
133
Shapiro T A, Fahey J W, Wade K L, Stephenson K K, Talalay P.
Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates
of cruciferous vegetables.
Cancer Epidemiol Biomarkers Prev.
1998;
7
1091-100
134
Shapiro T A, Fahey J W, Wade K L, Stephenson K K, Talalay P.
Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism
and excretion in humans.
Cancer Epidemiol Biomarkers Prev.
2001;
10
501-8
135
Zhang Y, Cho C G, Posner G H, Talalay P.
Spectroscopic quantitation of organic isothiocyanates by cyclocondensation with vicinal
dithiols.
Anal Biochem.
1992;
205
100-7
136
Zhang Y, Wade K L, Prestera T, Talalay P.
Quantitative determination of isothiocyanates, dithiocarbamates, carbon disulfide,
and related thiocarbonyl compounds by cyclocondensation with 1,2-benzenedithiol.
Anal Biochem.
1996;
239
160-7
137
Shapiro T A, Fahey J W, Dinkova-Kostova A T, Holtzclaw W D, Stephenson K K, Wade K L.
et al .
Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates:
a clinical phase I study.
Nutr Cancer.
2006;
55
53-62
138
Zhang Y, Talalay P, Cho C G, Posner G H.
A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and
elucidation of structure.
Proc Natl Acad Sci USA.
1992;
89
2399-403
139
Zhang Y, Tang L.
Discovery and development of sulforaphane as a cancer chemopreventive phytochemical.
Acta Pharmacol Sin.
2007;
28
1343-54
140
Talalay P, Dinkova-Kostova A T, Holtzclaw W D.
Importance of phase 2 gene regulation in protection against electrophile and reactive
oxygen toxicity and carcinogenesis.
Adv Enzyme Regul.
2003;
43
121-34
141
Nguyen T, Yang C S, Pickett C B.
The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical
stress.
Free Radic Biol Med.
2004;
37
433-41
142
Motohashi H, Yamamoto M.
Nrf2-Keap1 defines a physiologically important stress response mechanism.
Trends Mol Med.
2004;
10
549-57
143
Dinkova-Kostova A T, Holtzclaw W D, Kensler T W.
The role of Keap1 in cellular protective responses.
Chem Res Toxicol.
2005;
18
1779-91
144
Kensler T W, Wakabayashi N, Biswal S.
Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.
Annu Rev Pharmacol Toxicol.
2007;
47
89-116
145
Fahey J W, Talalay P.
Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes.
Food Chem Toxicol.
1999;
37
973-9
146
Dinkova-Kostova A T, Jenkins S N, Fahey J W, Ye L, Wehage S L, Stephenson K K. et
al .
Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by
sulforaphane-containing broccoli sprout extracts.
Cancer Lett.
2006;
240
243-52
147
Thejass P, Kuttan G.
Immunomodulatory activity of sulforaphane, a naturally occurring isothiocyanate from
broccoli (Brassica oleracea).
Phytomedicine.
2007;
14
538-45
148 Kim H J, Barajas B, Wang M, Nel A E. Nrf2 activation by sulforaphane restores
the age-related decrease of T(H)1 immunity: Role of dendritic cells. J Allergy Clin
Immunol, in press
149
Talalay P, Fahey J W, Healy Z R, Wehage S L, Benedict A L, Min C. et al .
Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation.
Proc Natl Acad Sci USA.
2007;
104
17 500-5
150
Dinkova-Kostova A T, Fahey J W, Wade K L, Jenkins S N, Shapiro T A, Fuchs E J. et
al .
Induction of the phase 2 response in mouse and human skin by sulforaphane-containing
broccoli sprout extracts.
Cancer Epidemiol Biomarkers Prev.
2007;
16
847-51
151
Reichrath J.
Vitamin D and the skin: an ancient friend, revisited.
Exp Dermatol.
2007;
16
618-25
152
Han S S, Keum Y S, Seo H J, Chun K S, Lee S S, Surh Y J.
Capsaicin suppresses phorbol ester-induced activation of NF-kappaB/Rel and AP-1 transcription
factors in mouse epidermis.
Cancer Lett.
2001;
164
119-26
153
Surh Y J.
Cancer chemoprevention with dietary phytochemicals.
Nat Rev Cancer.
2003;
3
768-80
154
Garssen J, Buckley T L, Van Loveren H.
A role for neuropeptides in UVB-induced systemic immunosuppression.
Photochem Photobiol.
1998;
68
205-10
155
Hart P H, Townley S L, Grimbaldeston M A, Khalil Z, Finlay-Jones J J.
Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression.
Methods.
2002;
28
79-89
156
Townley S L, Grimbaldeston M A, Ferguson I, Rush R A, Zhang S H, Zhou X F. et al .
Nerve growth factor, neuropeptides, and mast cells in ultraviolet-B-induced systemic
suppression of contact hypersensitivity responses in mice.
J Invest Dermatol.
2002;
118
396-401
157
Howes R A, Halliday G M, Barnetson R S, Friedmann A C, Damian D L.
Topical capsaicin reduces ultraviolet radiation-induced suppression of Mantoux reactions
in humans.
J Dermatol Sci.
2006;
44
113-5
158
Baur J A, Sinclair D A.
Therapeutic potential of resveratrol: the in vivo evidence.
Nat Rev Drug Discov.
2006;
5
493-506
159
Cantos E, Espín J C, Tomás-Barberán F A.
Postharvest induction modeling method using UV irradiation pulses for obtaining resveratrol-enriched
table grapes: a new ”functional” fruit?.
J Agric Food Chem.
2001;
49
5052-8
160
Versari A, Parpinello G P, Tornielli G B, Ferrarini R, Giulivo C.
Stilbene compounds and stilbene synthase expression during ripening, wilting, and
UV treatment in grape cv. Corvina.
J Agric Food Chem.
2001;
49
5531-6
161
Adhami V M, Afaq F, Ahmad N.
Suppression of ultraviolet B exposure-mediated activation of NF-kB in normal human
keratinocytes by resveratrol.
Neoplasia.
2003;
5
74-82
162
Park K, Lee J H.
Protective effects of resveratrol on UVB-irradiated HaCaT cells through attenuation
of the caspase pathway.
Oncol Rep.
2008;
19
413-7
163
Afaq F, Adhami V M, Ahmad N.
Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in
SKH-1 hairless mice.
Toxicol Appl Pharmacol.
2003;
186
28-37
164
Reagan-Shaw S, Afaq F, Aziz M H, Ahmad N.
Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet
B-mediated responses by resveratrol in SKH-1 hairless mouse skin.
Oncogene.
2004;
23
5151-60
165
Aziz M H, Reagan-Shaw S, Wu J, Longley B J, Ahmad N.
Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human
disease?.
FASEB J.
2005;
19
1193-5
166
Barthelman M, Chen W, Gensler H L, Huang C, Dong Z, Bowden G T.
Inhibitory effects of perillyl alcohol on UVB-induced murine skin cancer and AP-1
transactivation.
Cancer Res.
1998;
58
711-6
167
Haridas V, Hanausek M, Nishimura G, Soehnge H. et al .
Triterpenoid electrophiles (avicins) activate the innate stress response by redox
regulation of a gene battery.
J Clin Invest.
2004;
113
65-73
168
Creelman R A, Mullet J E.
Oligosaccharins, brassinolides, and jasmonates: nontraditional regulators of plant
growth, development, and gene expression.
Plant Cell.
1997;
9
1211-23
169
Strickland F M, Darvill A, Albersheim P, Eberhard S, Pauly M, Pelley R P.
Inhibition of UV-induced immune suppression and interleukin-10 production by plant
oligosaccharides and polysaccharides.
Photochem Photobiol.
1999;
69
141-7
170
Strickland F M.
Immune regulation by polysaccharides: implications for skin cancer.
J Photochem Photobiol B.
2001;
63
132-40
Albena T. Dinkova-Kostova
University of Dundee
Biomedical Research Centre
Ninewells Hospital and Medical School, Level 5
Dundee DD1 9SY
Scotland
United Kingdom
Phone: +44-1382-740-045
Fax: +44-1382-669-993
Email: a.dinkovakostova@dundee.ac.uk