Chemoprevention of Photocarcinogenesis by Resveratrol

描述（由申请人提供）： 在美国，非黑色素瘤皮肤癌，包括基底和 鳞状细胞癌是最常诊断的癌症形式， 据估计，100多万新的皮肤癌病例， 每年在美国确诊。因此，有必要加强我们的 为开发新的预防和治疗方法所作的努力 这种癌症类型。天然无毒化合物的化学预防 是预防该病发生的潜在策略。藜芦醇 （3，5，4 '-trihydroxystilbene），一种在葡萄中发现的植物抗氧化剂，红 葡萄酒、浆果和花生被证明可以提供癌症的化学预防 在化学诱导的小鼠皮肤癌发生中的作用。经典 皮肤癌的化学致癌模型被认为是很少的，如果 与人类皮肤癌的任何相关性， 紫外线（UV）辐射是人类皮肤癌的主要原因。我们 初步研究表明局部应用白藜芦醇 预防SENCAR小鼠中化学诱导的皮肤癌发生。的 白藜芦醇赋予的生物效应的分子机制是 没有被很好地理解。我们最近的研究（临床癌症研究，接受 已证明白藜芦醇治疗人类 表皮样癌（A431）细胞导致细胞周期蛋白激酶的诱导 抑制剂WAF 1/p21抑制细胞周期蛋白（D1/D2）-cdk 6，细胞周期蛋白（D1/D2）-cdk 4， 细胞周期蛋白E-cdk 2复合物，从而导致细胞的G1期停滞 周期和细胞的凋亡性死亡。我们还发现白藜芦醇 治疗引起精母细胞瘤（pRb）-E2 FDP机制的调节， A431细胞的G1期阻滞和凋亡。当前应用程序基于 这些新的观察，并旨在调查 白藜芦醇对UVB介导皮肤的化学预防作用 致癌作用，以及这种以食物为基础的 多酚类抗氧化剂赋予癌症化学预防作用。中央 本申请中提出的工作假设是白藜芦醇将 通过调节光致癌作用而赋予化学预防作用 cki-cyclin-cdk网络介导的细胞周期调控和凋亡。在这 研究中，我们将首先确定白藜芦醇的癌症化学预防潜力 抗UVB介导的损伤，包括SKH-1无毛小鼠的皮肤肿瘤发生 小鼠然后我们将进行研究，以评估CKI-cyclic-CDK的参与 网络作为白藜芦醇在森林中化学预防作用的机制 UVB介导的反应和SKH-1无毛小鼠的皮肤肿瘤发生。 成功完成此申请将定义i） 白藜芦醇对皮肤癌的化学预防/治疗潜力， ii）白藜芦醇生物效应的分子机制。这可能 为制定新的预防战略铺平道路， 也可能治疗皮肤癌和其他上皮癌。

DESCRIPTION (provided by applicant): 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.