In the United States, non-melanoma skin cancer that includes basal- and squamous-cell carcinoma is the most frequently diagnosed form of cancer and, according to an estimate, more than a million new cases of skin cancers are diagnosed annually in the USA. Therefore, it is warranted to intensify our efforts for the development of novel approaches for prevention and therapy of this cancer type. Chemoprevention by naturally occurring non-toxic compounds is a potential strategy to prevent the occurrence of the disease. Resveratrol (3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found in grapes, red wines, berries and peanuts has been shown to afford cancer chemopreventive effects in chemically-induced murine skin carcinogenesis. The classical chemical carcinogenesis model of skin cancer is regarded to have little, if any, relevance to humans skin cancers because the excessive exposure to solar ultraviolet (UV) radiation is the major cause of human skin cancers. Our preliminary studies have shown that topical application of resveratrol prevents against chemically induced skin carcinogenesis in SENCAR mice. The molecular mechanism(s) of the biological effects imparted by resveratrol is not well understood. Our recent studies (Clinical Cancer Research, accepted for-publication), have demonstrated that resveratrol treatment to human epidermoid carcinoma (A431) cells results in an induction of the cyclinkinase inhibitor WAFl/p21 that inhibits cyclin (D1/D2)-cdk 6, cyclin (D1/D2)-cdk 4, cyclin E-cdk 2 complexes, thereby resulting in a G1-phase arrest of the cell cycle and an apoptotic death of the cells. We have also found that resveratrol treatment causes a modulation in refinoblastoma (pRb)-E2FDP machinery, during G1-phase arrest and apoptosis of A431 cells. The current application is based on these novel observations, and is designed to investigate the chemopreventive potential of resveratrol against UVB-mediated skin carcinogenesis, and the molecular mechanism(s) by which this food-based polyphenolic antioxidant imparts cancer chemopreventive effects. The central hypothesis of the work proposed in this application is that resveratrol will impart chemopreventive effects against photocarcinogenesis via modulating cki-cyclin-cdk network-mediated cell cycle regulation and apoptosis. In this study, we will first establish cancer chemopreventive potential of resveratrol against UVB-mediated damages including skin tumorigenesis in SKH-1 hairless mice. We will then conduct studies to assess the involvement of cki-cyclic-cdk network as a mechanism of chemopreventive effects of resveratrol during for UVB-mediated responses and skin tumorigenesis in SKH-1 hairless mice. Successful completion of this application will define i) the chemopreventive/therapeutic potential of resveratrol against skin cancer, and ii) molecular mechanism(s) of the biological effects of Resveratrol. This may pave the way for the development of novel strategies for prevention and possibly treatment of skin cancer and other epithelial cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA098368-01
Application #
6561874
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Perloff, Marjorie
Project Start
2002-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$72,750
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Reagan-Shaw, Shannon; Breur, Jorien; Ahmad, Nihal (2006) Enhancement of UVB radiation-mediated apoptosis by sanguinarine in HaCaT human immortalized keratinocytes. Mol Cancer Ther 5:418-29
Aziz, Moammir Hasan; Reagan-Shaw, Shannon; Wu, Jianqiang et al. (2005) Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? FASEB J 19:1193-5
Reagan-Shaw, Shannon; Afaq, Farrukh; Aziz, Moammir Hasan et al. (2004) Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin. Oncogene 23:5151-60
Adhami, Vaqar Mustafa; Aziz, Moammir Hasan; Reagan-Shaw, Shannon R et al. (2004) Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. Mol Cancer Ther 3:933-40
Adhami, Vaqar Mustafa; Afaq, Farrukh; Ahmad, Nihal (2003) Suppression of ultraviolet B exposure-mediated activation of NF-kappaB in normal human keratinocytes by resveratrol. Neoplasia 5:74-82
Adhami, Vaqar Mustafa; Aziz, Moammir Hasan; Mukhtar, Hasan et al. (2003) Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratinocytes. Clin Cancer Res 9:3176-82