Chronic exposure of solar ultraviolet (UV) radiation to human skin is more than primarily responsible for one million new cases of nonmelanoma skin cancer each year in the USA, making it the most prevalent environmental carcinogen known for humans. It is well documented that UV radiation is a potent producer of reactive oxygen species and can act as tumor initiator and promoter. UV-induced oxidative stress plays a crucial role in activation of cellular signal transduction pathways which are implicated in various skin diseases including cancer. There have been concerted efforts to identify newer and effective chemopreventive agents that can prevent UV carcinogenesis in humans. In earlier studies, we have shown that silymarin, a plant flavonoid from milk thistle (Silybum marianum L.), has potent anti-photocarcinogenic and anti-oxidant properties in an animal model (Katiyar et al, JNCI, 89:556-566, 1997). The current proposal is designed to determine the mechanism of prevention and identification of the cellular targets responsible for the prevention of photocarcinogenesis by silymarin treatment in the mouse model. The hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to this hypothesis is that topical treatment of silymarin to SKH-1 hairless mice will prevent UVB radiation induced oxidative stress, and thus oxidative stress-mediated activation of EGFR and MAPK signaling pathways which will result in reduction of skin cancer incidence. The following specific aims are proposed to test this hypothesis.
In Specific Aim -l, experiments will be conducted to determine whether topical treatment of silymarin will prevent UVB radiation induced: (a) depletion of cutaneous antioxidant defense components, such as glutathione peroxidase, catalase and glutathione (GSH), and (b) markers of oxidative stress, such as release of H202, nitric oxide and lipid peroxidation.
In Specific Aim -II, we will determine whether treatment of silymarin will prevent UVB-induced oxidative stress mediated phosphorylation of EGFR, and MAPK such as ERKI/2, JNK and p38 signaling pathways. The results obtained from this study would lead to the generation of new knowledge by which silymarin exert's its chemopreventive effects, and will identify new methods and strategies for the prevention of solar UV radiation-induced skin cancer in humans, which may result to protect and prolong the human health and lives.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA105368-01
Application #
6730073
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (O1))
Program Officer
Steele, Vernon E
Project Start
2003-09-30
Project End
2005-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$72,500
Indirect Cost
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Vaid, Mudit; Katiyar, Santosh K (2010) Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (Review). Int J Oncol 36:1053-60
Katiyar, Santosh K; Meleth, Sreelatha; Sharma, Som D (2008) Silymarin, a flavonoid from milk thistle (Silybum marianum L.), inhibits UV-induced oxidative stress through targeting infiltrating CD11b+ cells in mouse skin. Photochem Photobiol 84:266-71
Katiyar, Santosh K (2007) Interleukin-12 and photocarcinogenesis. Toxicol Appl Pharmacol 224:220-7
Katiyar, Santosh K (2007) UV-induced immune suppression and photocarcinogenesis: chemoprevention by dietary botanical agents. Cancer Lett 255:1-11
Katiyar, Suchitra; Elmets, Craig A; Katiyar, Santosh K (2007) Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem 18:287-96
Baliga, Manjeshwar S; Katiyar, Santosh K (2006) Chemoprevention of photocarcinogenesis by selected dietary botanicals. Photochem Photobiol Sci 5:243-53
Meeran, Syed M; Katiyar, Suchitra; Elmets, Craig A et al. (2006) Silymarin inhibits UV radiation-induced immunosuppression through augmentation of interleukin-12 in mice. Mol Cancer Ther 5:1660-8
Katiyar, Santosh K; Roy, Anshu M; Baliga, Manjeshwar S (2005) Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol Cancer Ther 4:207-16
Katiyar, Santosh K (2005) Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review). Int J Oncol 26:169-76
Mantena, Sudheer K; Meeran, Syed M; Elmets, Craig A et al. (2005) Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. J Nutr 135:2871-7

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