Prevention of Photocarcinogenesis by antioxidant

通过抗氧化剂预防光致癌

• 批准号: 6545219
• 负责人: SANTOSH K KATIYAR
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545219
• 关键词: antioxidants; biological signal transduction; biopsy; cancer prevention; catechols; caucasian American; chemoprevention; clinical research; epidermal growth factor; female; flavones; free radical oxygen; growth factor receptors; human subject; human therapy evaluation; mitogen activated protein kinase; patient oriented research; phosphorylation; plant extracts; radiation related neoplasm /cancer; skin neoplasms; solar radiation; tea; tissue /cell culture; topical drug application; ultraviolet radiation

DESCRIPTION (provided by applicant)Chronic exposure to solar ultraviolet (UV) radiation, particularly UVB (290-320 nm), is primarily responsible for more than 1,000,000 new cases of nonmelanoma skin cancer each year in the USA alone, making it the most hazardous environmental carcinogen known for humans. Thus, there is an urgent need to develop strategies to prevent the occurrence of cutaneous malignancies. It is well documented that UV radiation is a potent producer of reactive oxygen species (ROS), which play a critical role in cellular signal transduction pathways. Phosphorylation of cell signaling molecules is implicated in various skin diseases including skin cancer. One approach to reduce the risk of UV-induced ROS-mediated skin cancer is the use of antioxidant agents. Several studies led to a strong suggestion that the regular intake of polyphenolic antioxidants from green tea may be an appropriate and effective strategy to prevent some forms of human cancers. We and others have shown that a potyphenolic fraction isolated from green tea, and particularly its major and the most effective chemopreventive antioxidant constituent (-)-epigallocatechin-3-gallate (EGCG) has remarkable preventive effects against UV-induced skin carcinogenesis in mouse model. We found that treatment with EGCG to human skin before UV exposure inhibits UV-induced oxidative stress. The aim of this application is to defme the mechanism through which EGCG would prevent UV-induced oxidative stress-mediated cell signaling pathways in human skin. The central hypothesis to be tested in this proposal is that UV-induced oxidative stress causes phosphorylation of epidermal growth factor receptor (EGFR), and mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinase (ERK1/2) and p38 in human skin. The corollary to our hypothesis is that topical treatment with EGCG before UV exposure of the skin will prevent UV radiation-induced oxidative stress, which in turn will inhibit oxidative stress-mediated phosphorylation of cellular signaling events. The inhibition of UV-induced oxidative stress- mediated signaling pathways by EGCG will prevent the occurrence of skin cancer. Validation of this hypothesis would have major implications for the importance of oxidative stress-mediated skin cancer, as well as offering promise for the development of novel intervention approaches to mitigate UV-induced cellular signaling events linked to skin cancer incidence by the use of antioxidants.

描述（由申请人提供）长期暴露于太阳紫外线（UV）辐射，特别是UVB（290-320 nm），仅在美国每年就造成超过1，000，000例新的非黑色素瘤皮肤癌病例，使其成为已知对人类最危险的环境致癌物。因此，迫切需要制定预防皮肤恶性肿瘤发生的策略。紫外线辐射是活性氧（reactive oxygen species，ROS）的重要来源，在细胞信号转导中起重要作用。细胞信号分子的磷酸化与包括皮肤癌在内的各种皮肤病有关。降低紫外线诱导的活性氧介导的皮肤癌风险的一种方法是使用抗氧化剂。几项研究强烈表明，定期摄入绿色茶中的多酚类抗氧化剂可能是预防某些形式的人类癌症的适当而有效的策略。我们和其他人已经表明，从绿色茶中分离的多酚级分，特别是其主要和最有效的化学预防性抗氧化剂成分（-）-表没食子儿茶素-3-没食子酸酯（EGCG），在小鼠模型中对UV诱导的皮肤癌发生具有显著的预防作用。我们发现，在紫外线照射前用EGCG处理人体皮肤可以抑制紫外线诱导的氧化应激。本申请的目的是确定EGCG通过其阻止人类皮肤中UV诱导的氧化应激介导的细胞信号传导途径的机制。在这个建议中要测试的中心假设是，紫外线诱导的氧化应激导致表皮生长因子受体（EGFR）和丝裂原活化蛋白激酶（MAPK），如细胞外信号调节激酶（ERK 1/2）和p38在人类皮肤中的磷酸化。我们假设的推论是，在皮肤暴露于UV之前用EGCG局部治疗将防止UV辐射诱导的氧化应激，这反过来将抑制氧化应激介导的细胞信号传导事件的磷酸化。EGCG抑制紫外线诱导的氧化应激介导的信号通路将防止皮肤癌的发生。这一假设的验证将对氧化应激介导的皮肤癌的重要性产生重大影响，并为开发新的干预方法提供希望，以减轻紫外线诱导的细胞信号传导事件与皮肤癌的发病率通过使用抗氧化剂。