Proanthocyanidins: Novel Skin Cancer Preventive Agent

描述(申请人提供)：太阳紫外线(UV)辐射，特别是UVB(290-320 nm)对人体皮肤的长期暴露是美国每年100多万例非黑色素瘤皮肤癌新病例的主要原因，使其成为人类已知的最普遍的环境致癌物质。紫外线辐射是一种有效的产生活性氧的物质，它既是谣言的始发者，也是谣言的促进者。紫外线诱导的氧化应激在细胞信号转导通路的激活中起着至关重要的作用，这些信号转导通路与包括癌症在内的各种皮肤病有关。已经共同努力寻找新的和有效的化学预防药物，以防止紫外线辐射过度暴露的不利影响。在初步研究中，我们观察到从葡萄籽中分离出的原花青素(GSP)在动物模型中能够显著防止光癌发生。因此，目前的建议旨在确定GSP治疗在SKH-1无毛小鼠模型中预防光癌发生的机制。这项建议中要检验的假设是，UVB暴露在皮肤中会诱导氧化应激，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)信号通路的激活，从而导致光致癌事件的诱导。这一假设的推论是，小鼠饮食中摄入GSP可以防止UVB辐射诱导的氧化应激，从而防止氧化应激介导的EGFR和MAPK信号通路的激活，从而降低皮肤癌的发病率。为了检验这一假说，本文提出了以下具体目标。在特定的目标-1中，我们将研究饮食中添加GSP是否可以防止UVB辐射引起的：(A)皮肤抗氧化防御酶，如谷胱甘肽过氧化物酶、过氧化氢酶、超氧化物歧化酶和谷胱甘肽水平的耗竭，以及(B)氧化应激的标志物，如H2C和Gt；2，以及小鼠皮肤中一氧化氮的产生、脂质过氧化和蛋白质氧化。在特定的AIM-II中，我们将在体内和体外系统中研究饮食中添加GSP是否可以阻止UVB诱导的氧化应激介导的EGFR和MAPK蛋白的磷酸化，如细胞外信号调节激酶(ERK1/2)、c-Jun-N末端激酶(INK)和p38信号通路。这项研究的结果可能导致产生新的知识，通过GSP发挥其光保护作用，并将找到新的膳食植物补充剂，可用作预防太阳紫外线辐射诱导的人类皮肤癌的补充方法。预防皮肤癌的风险将导致保护和延长人类的健康和生命。

DESCRIPTION (provided by applicant): Chronic exposure of solar ultraviolet (UV) radiation, particularly UVB (290-320 nm), to human skin is primarily responsible for more than one million new cases of nonmelanoma skin cancer each year in the USA, making it the most prevalent environmental carcinogen known for humans. It is well documented that UV radiation is a potent producer of reactive oxygen species (ROS) and can act as both rumor initiator and promoter. UV-induced oxidative stress plays a crucial role in activation of cellular signal transduction pathways, which are implicated in various skin diseases including cancer. There have been concerted efforts to identify newer and effective chemopreventive agents that can protect against the adverse effects of UV radiation overexposure. In preliminary studies, we observed that dietary feeding of procyanidins isolated from grape seeds (GSP) resulted in significant prevention of photocarcinogenesis in animal model. The current proposal is therefore designed to define the mechanism of prevention of photocarcinogenesis by GSP treatment in SKH-1 hairless mouse model. The hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to this hypothesis is that dietary feeding of GSP to mice will prevent UVB radiation induced oxidative stress, and thus oxidative stress-mediated activation of EGFR and MAPK signaling pathways which will result in reduction of skin cancer incidence. Following specific aims are proposed to test this hypothesis. In Specific Aim-1, we will examine whether dietary feeding of GSP will prevent UVB radiation induced: (a) depletion of cutaneous antioxidant defense enzymes, such as glutathione peroxidase, catalase, superoxide dismutase and glutathione level, and (b) markers of oxidative stress, such as H2C>2 and nitric oxide production, lipid peroxidation and protein oxidation in mouse skin. In Specific Aim-II, we will examine whether dietary feeding of GSP prevents UVB-induced oxidative stress-mediated phosphorylation of EGFR, and MAPK proteins such as extracellular signal-regulated kinase (ERK1/2), c-Jun-N-terminal kinase (INK) and p38 signaling pathways in vivo mouse skin, and in vitro system. The results obtained from this study may lead to the generation of new knowledge by which GSP exert its photoprotective effects, and will identify new dietary botanical supplement which can be used as a complementary approach for the prevention of solar UV radiation-induced skin cancer in humans. Prevention of skin cancer risk will result to protect and prolong the human health and lives.