Inhibition of skin cancer by caffeine: Effects on late stages of carcinogenesis

描述（由申请人提供）：阳光诱发的皮肤癌是美国最常见的癌症。在早期的研究中，我们用UVB治疗SKH-1小鼠，每周两次，持续20周。这些被启动的小鼠没有肿瘤，但它们在接下来的几个月里有很高的患肿瘤的风险（高风险小鼠）。对这些高风险小鼠局部应用咖啡因，每周五天，可以抑制癌变，选择性地增加肿瘤的细胞凋亡，但在远离肿瘤的表皮区域没有作用。我们的主要假设是，咖啡因通过抑制ATR/ chk1依赖的G2/M细胞周期检查点，导致细胞过早有丝分裂和死亡，从而诱导细胞凋亡。在准备咖啡因对人体影响的转化研究时，我们评估了公众常用的四种商业保湿霜的致瘤性。在高风险小鼠局部应用几个月后，这四种药物都有致瘤活性。为了克服这一障碍，我们开发了一种新的自定义混合乳膏，它缺乏致瘤活性，可用于人类的转化研究。我们计划实现以下具体目标：1。确定在我们新开发的非致瘤性定制混合乳膏中局部应用咖啡因对uvb预处理的高风险SKH-1小鼠的致癌作用，并研究该治疗对表皮局灶性增生区域和肿瘤中细胞凋亡、增殖和ATR/Chk1信号转导途径的影响。还将研究口服咖啡因的效果。2. 通过研究短期治疗后（例如局部应用咖啡因3小时、6小时、24小时、48小时、7天或14天）对表皮局灶性增生性区域和肿瘤中基于Aim 1的关键分子标记物的影响，确定咖啡因作用的主要靶点或早期事件。3. 启动一项转化研究，以确定局部应用咖啡因对人类皮肤光化性角化病的细胞凋亡、增殖和ATR/Chk1通路的影响。Aim 1研究中确定的关键分子标记将在局部应用咖啡因或安慰剂两周前后的大型角化病活检中确定。公共卫生相关性：我们提出的咖啡因对紫外线诱导的癌症形成的机制研究是开发预防阳光诱导皮肤癌新方法的重要步骤。我们对咖啡因影响的研究可能对摄入含咖啡因饮料和巧克力的个人也很重要。

DESCRIPTION (provided by applicant): Sunlight-induced skin cancer is the most prevalent cancer in the United States. In earlier studies we treated SKH-1 mice with UVB twice a week for 20 weeks. These initiated mice have no tumors, but they have a high risk of developing tumors during the next several months (high risk mice). Topical applications of caffeine 5 days a week to these high risk mice inhibited carcinogenesis and selectively increased apoptosis in the tumors but not in areas of the epidermis away from the tumors. Our leading hypothesis is that caffeine induces apoptosis by inhibition of the ATR/Chk1-dependent G2/M cell cycle checkpoint leading to premature mitosis and cell death. In preparation for translational studies on the effects of caffeine in humans, we evaluated the tumorigenicity of four commercial moisturizing creams that are commonly used by the public. All four had tumorigenic activity when applied topically for several months to high risk mice. To overcome this obstacle, we developed a novel Custom Blend cream that lacks tumorigenic activity and can be used for translational studies in humans. We plan to pursue the following specific aims: 1. Determine the effects of topical applications of caffeine in our newly developed non-tumorigenic Custom Blend cream on carcinogenesis in UVB-pretreated high risk SKH-1 mice and study the effects of the treatment on apoptosis, proliferation and the ATR/Chk1 signal transduction pathway in focal hyperplastic areas of the epidermis and in tumors. The effects of oral administration of caffeine will also be studied. 2. Determine the primary targets or early events for the action of caffeine by studying its effect on key molecular markers based on Aim 1 in epidermal focal hyperplastic areas and tumors after short term treatment (e.g. with topically applied caffeine for 3 hr, 6 hr, 24 hr, 48 hr, 7 days, or 14 days). 3. Initiate a translational study to determine the effects of topical applications of caffeine on apoptosis, proliferation and the ATR/Chk1 pathway in actinic keratoses in human skin. Key molecular markers identified by research in Aim 1 will be determined in biopsies of large keratoses before and after two weeks of topical applications of caffeine or placebo. PUBLIC HEALTH RELEVANCE:Our proposed mechanistic studies on the effects of caffeine on ultraviolet light-induced cancer formation are important steps on the road to the development of a novel approach for the prevention of sunlight-induced skin cancer. Our studies on the effects of caffeine may also have importance for individuals ingesting caffeine-containing beverages and chocolate.