Effect of caffeine on UVB-induced skin cancer

描述（由申请人提供）：阳光诱导的皮肤癌是美国最常见的癌症，UVB是这些癌症的主要原因。早期的研究表明，口服或局部施用咖啡因抑制UVB诱导的小鼠皮肤癌的发生，通过选择性地增强UVB处理的表皮和表皮肿瘤中的细胞凋亡，而不是在正常表皮中。这些作用可以通过不依赖于p53的机制发生。本提案的主要目标是确定咖啡因在UVB处理的表皮和UVB诱导的肿瘤中的体内细胞凋亡效应的机制以及在人类中启动翻译研究。我们计划实现以下具体目标：1.确定在用UVB单次照射后立即局部应用咖啡因对UVB诱导的细胞凋亡和UVB诱导的ATR/Chk 1信号转导途径在野生型小鼠、p53敲除小鼠、ATR和Chk 1显性阴性小鼠和Chk 1单倍缺陷小鼠表皮中活化的时间过程的影响。还将确定咖啡因增强细胞周期早期有丝分裂的不适当启动的可能性。2.确定局部应用咖啡因对细胞凋亡和ATR/Chk 1信号转导通路的影响，以及UVB诱导的肿瘤和远离肿瘤的表皮区域中不适当早期启动有丝分裂的可能性。3.启动一项初步研究，以确定在用UVB单次照射后立即局部应用咖啡因对UVB诱导的细胞凋亡以及人皮肤表皮中野生型p53和ATR/Chk 1信号转导通路的水平的影响。由于咖啡因被大部分人群摄入咖啡，茶，软饮料和巧克力中，因此对咖啡因潜在抗癌作用机制的研究可能对癌症预防具有广泛的人类意义。该提案还包括第一项人类研究，该研究可能会导致一种预防人类日光诱导皮肤癌的新方法。

DESCRIPTION (provided by applicant): Sunlight-induced skin cancer is the most prevalent cancer in the United States, and UVB is primarily responsible for these cancers. Earlier studies indicated that oral or topical administration of caffeine inhibits UVB-induced skin carcinogenesis in mice by enhancing apoptosis selectively in UVB-treated epidermis and in epidermal tumors but not in normal epidermis. These effects can occur by a p53 independent mechanism. Identification of mechanisms for the in vivo apoptotic effect of caffeine in UVB-treated epidermis and in UVB-induced tumors as well as the initiation of translational studies in humans are major goals of the present proposal. We plan to pursue the following specific aims: 1. Determine the effects of topical application of caffeine immediately after a single irradiation with UVB on the time course for UVB-induced apoptosis and for UVB-induced activation of the ATR/Chk1 signal transduction pathway in the epidermis of wild type mice, p53 knockout mice, ATR and Chk1 dominant negative mice and Chk1 haploinsufficient mice. The possibility that caffeine enhances the inappropriate initiation of mitosis early in the cell cycle will also be determined. 2. Determine the effects of topically applied caffeine on apoptosis and the ATR/Chk1 signal transduction pathway as well as the possibility of inappropriate early initiation of mitosis in UVB-induced tumors and in areas of the epidermis away from tumors. 3. Initiate a pilot study to determine the effects of topical application of caffeine immediately after a single irradiation with UVB on UVB-induced apoptosis as well as the levels of wild type p53 and the ATR/Chk1 signal transduction pathway in the epidermis of human skin. Since caffeine is ingested by large segments of the population in coffee, tea, soft drinks and chocolate, research on mechanisms of the potential anticancer effects of caffeine may have broad human significance for cancer prevention. The proposal also includes the first human studies on a path that may lead to a novel way of preventing sunlight-induced skin cancer in humans.