Prevention of Photocarcinogenesis by antioxidant

描述(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)，主要导致每年仅在美国就有超过1,000,000例新的非黑色素瘤皮肤癌病例，使其成为人类已知的最危险的环境致癌物质。因此，迫切需要制定预防皮肤恶性肿瘤发生的策略。研究表明，紫外线辐射是一种产生活性氧的有效物质，而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各种皮肤病有关。减少紫外线诱导的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，定期摄入绿茶中的多酚抗氧化剂可能是预防某些形式的人类癌症的适当和有效的策略。我们和其他人已经证明，从绿茶中分离出的一种酚类成分，特别是其主要和最有效的化学预防抗氧化剂成分(-)-表没食子儿茶素没食子酸酯(EGCG)，对紫外线诱导的小鼠皮肤癌具有显著的预防作用。我们发现，在紫外线照射前对人体皮肤进行EGCG处理可以抑制紫外线诱导的氧化应激。这项应用的目的是为了阐明EGCG阻止紫外线诱导的氧化应激介导的人体皮肤细胞信号通路的机制。这项提议要检验的中心假设是，紫外线诱导的氧化应激导致人皮肤中表皮生长因子受体(EGFR)和丝裂原激活蛋白激酶(MAPK)的磷酸化，如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使用EGCG局部治疗将防止紫外线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事件的磷酸化。EGCG抑制紫外线诱导的氧化应激介导的信号转导通路，可预防皮肤癌的发生。这一假说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，以通过使用抗氧化剂来减轻紫外线诱导的与皮肤癌发病相关的细胞信号事件。

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.