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 鳞状细胞癌是最常见的癌症诊断形式， 据估计，超过100万新的皮肤癌病例是 在美国每年确诊一次。因此，有理由加强我们的 努力开发新的预防和治疗方法 这种癌症类型。天然无毒化合物的化学预防 是预防这种疾病发生的一种潜在策略。白藜芦醇 (3，5，4‘-三羟基二苯乙烯)，一种在葡萄中发现的植物防御素抗氧化剂，红葡萄酒 葡萄酒、浆果和花生被证明可以提供癌症化学预防 化学诱导小鼠皮肤癌的作用。古典的 皮肤癌的化学致癌模型被认为几乎没有，如果 任何，都与人类皮肤癌有关，因为过度暴露在阳光下 紫外线辐射是人类皮肤癌的主要原因。我们的 初步研究表明，局部应用白藜芦醇 预防化学诱导的Sencar小鼠皮肤癌的发生。这个 白藜芦醇生物学作用的分子机制(S) 不是很清楚。我们最近的研究(临床癌症研究，接受 )，证明了白藜芦醇对人类的治疗 表皮样癌(A431)细胞诱导细胞周期蛋白激酶 抑制细胞周期蛋白(d1/d2)-cdk6、细胞周期蛋白(d1/d2)-cdk4的抑制剂WAFL/p21， Cyclin E-cdk2复合体，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)-E2FDP机制的调节 A431细胞的G1期停滞和凋亡。当前应用程序基于 关于这些新颖的观察，并被设计用来研究 白藜芦醇对中波紫外线皮肤的化学预防作用 致癌，以及这种以食物为基础的分子机制(S 多酚类抗氧化剂具有化学预防癌症的作用。中环 本申请中提出的工作假设是白藜芦醇将 通过调控传递光致癌的化学预防作用 CKI-Cyclin-CDK网络介导的细胞周期调控和细胞凋亡。在这 研究，我们将首先建立白藜芦醇的癌症化学预防潜力 抗中波紫外线介导的损伤，包括无毛SKH-1的皮肤肿瘤形成 老鼠。然后，我们会进行研究，以评估长江基建-环发局的参与。 网络作为白藜芦醇化学预防作用的机制 UVB介导的反应与SKH-1无毛小鼠皮肤肿瘤的发生。 成功完成此申请将定义i) 白藜芦醇对皮肤癌的化学预防/治疗作用 白藜芦醇生物学作用的分子机制(S)。今年5月 为制定新的预防和预防战略铺平道路 可能治疗皮肤癌和其他上皮性癌症。

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.