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

咖啡因抑制皮肤癌：对癌发生晚期的影响

• 批准号: 8257067
• 负责人: Yaoping Lu
• 金额: $ 28.05万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257067
• 关键词: Actinic keratosis; Apoptosis; Applications Grants; Area; Beverages; Biopsy; Budgets; Caffeine; Cell Death; Cells; Chocolate; Consultations; Cream; Custom; DNA Damage; Data; Development; Drops; Epidermis; Event; Funding; G2/M Checkpoint Pathway; Grant; Health; Human; Hyperplasia; Individual; Inhibition of Apoptosis; Keratosis; Laboratories; Lesion; Malignant Neoplasms; Mitosis; Mus; Mutation; Oral Administration; Pathway interactions; Placebos; Preparation; Prevention; Research; Signal Transduction Pathway; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Staging; Study Section; Testing; Topical application; Tumorigenicity; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; base; carcinogenesis; cyclin B1; high risk; in vivo; irradiation; molecular marker; mouse model; novel; novel strategies; premature; sunlight-induced; translational study; treatment effect; tumor; tumorigenesis; tumorigenic

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.

描述（由申请人提供）：阳光引起的皮肤癌是美国最普遍的癌症。在较早的研究中，我们每周两次用UVB治疗SKH-1小鼠20周。这些启动的小鼠没有肿瘤，但是在接下来的几个月中，它们有肿瘤的高风险（高风险小鼠）。每周5天咖啡因对这些高风险小鼠的局部应用抑制了癌症的发生，并有选择地增加肿瘤中的凋亡，但在表皮区域却没有远离肿瘤。我们的主要假设是，咖啡因通过抑制ATR/CHK1依赖性G2/M细胞周期检查点诱导凋亡，从而导致过度有丝分裂和细胞死亡。为了准备有关咖啡因在人类影响的翻译研究，我们评估了公众常用的四种商业保湿霜的肿瘤性。当局部局部应用几个月以高风险小鼠时，这四个均具有致瘤活性。为了克服这一障碍，我们开发了一种新型的定制混合霜，该乳霜缺乏肿瘤性活性，可用于人类的翻译研究。我们计划追求以下特定目的：1。确定咖啡因在我们新开发的我们新开发的非肿瘤定制混合霜对UVB预处理的高风险SKH-1小鼠中癌变的影响，并研究治疗对凋亡，扩散，繁殖和ATR/CHK1信号传输途径的影响。还将研究口服咖啡因的作用。 2。通过研究短期治疗后表皮局灶性增生区域和肿瘤的AIM 1对咖啡因作用的主要目标或早期事件（例如，在局部施用咖啡因3小时，6小时，6小时，24小时，48小时，48小时，7天或14天）。 3。启动一项翻译研究，以确定咖啡因对人类皮肤阳光性角化作用中凋亡，增殖和ATR/CHK1途径的局部应用的影响。 AIM 1中通过研究确定的关键分子标记将在咖啡因或安慰剂的局部局部应用前后的活检中确定。公共卫生相关性：我们提出的关于咖啡因对紫外线光引起的癌症形成的影响的机理研究是开发一种新方法预防阳光诱发的皮肤癌的重要步骤。我们对咖啡因作用的研究也可能对摄入含咖啡因饮料和巧克力的人具有重要意义。