Prevention of Photocarcinogenesis by antioxidant

通过抗氧化剂预防光致癌

• 批准号: 6607558
• 负责人: SANTOSH KUMAR 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607558
• 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.

长期暴露于太阳紫外线（UV）辐射，特别是UVB (290-320 nm)，仅在美国每年就导致超过100万例新发非黑色素瘤皮肤癌，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。有充分证据表明，紫外线辐射是活性氧（ROS）的有效生产者，活性氧在细胞信号转导途径中起着关键作用。细胞信号分子的磷酸化与包括皮肤癌在内的多种皮肤病有关。降低紫外线诱导ros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，经常从绿茶中摄入多酚类抗氧化剂可能是预防某些人类癌症的适当而有效的策略。我们和其他人已经证明，从绿茶中分离出的多酚组分，特别是其主要和最有效的化学预防抗氧化成分(-)-表没食子儿茶素-3-没食子酸酯（EGCG）在小鼠模型中对紫外线诱导的皮肤癌有显著的预防作用。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。本应用的目的是确定EGCG阻止紫外线诱导的人体皮肤氧化应激介导的细胞信号通路的机制。本研究的核心假设是，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）的磷酸化，如人类皮肤中的细胞外信号调节激酶（ERK1/2）和p38。我们假设的推论是，在皮肤暴露于紫外线之前用EGCG局部治疗可以防止紫外线辐射诱导的氧化应激，从而抑制氧化应激介导的细胞信号事件的磷酸化。EGCG抑制紫外线诱导的氧化应激介导的信号通路，可预防皮肤癌的发生。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，同时也为开发新的干预方法提供了希望，通过使用抗氧化剂来减轻紫外线诱导的与皮肤癌发病率相关的细胞信号事件。