Proanthocyanidins: Novel Skin Cancer Preventive Agent

描述（由申请人提供）：人类皮肤长期暴露于太阳紫外线（UV）辐射，特别是UVB (290-320 nm)，是美国每年超过100万例新发非黑色素瘤皮肤癌的主要原因，使其成为人类已知的最普遍的环境致癌物。有充分的证据表明，紫外线辐射是活性氧（ROS）的有效生产者，可以作为谣言的发起者和促进者。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，这与包括癌症在内的各种皮肤疾病有关。人们一直在共同努力，以确定更新和有效的化学预防剂，以防止紫外线辐射过度暴露的不利影响。在初步研究中，我们观察到饲料中添加葡萄籽原花青素（GSP）对动物模型的光致癌作用有显著的预防作用。因此，本研究旨在明确GSP在SKH-1无毛小鼠模型中预防光致癌的机制。本研究要验证的假设是，UVB暴露于皮肤会诱导氧化应激，从而激活表皮生长因子受体（EGFR）和丝裂原活化蛋白激酶（MAPK）信号通路，从而诱导光致癌事件。这一假设的推论是，给小鼠喂食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。提出以下具体目标来检验这一假设。在Specific Aim-1中，我们将研究饲粮中添加GSP是否会预防UVB辐射诱导的：(a)皮肤抗氧化防御酶的消耗，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；(b)氧化应激标志物，如小鼠皮肤中H2C bbb2和一氧化氮的产生、脂质过氧化和蛋白质氧化。在Specific Aim-II中，我们将研究膳食中添加GSP是否会阻止uvb诱导的氧化应激介导的EGFR和MAPK蛋白磷酸化，如细胞外信号调节激酶（ERK1/2）、c- jun - n-末端激酶（INK）和p38信号通路在体内小鼠皮肤和体外系统中。本研究的结果可能为GSP发挥其光防护作用提供新的知识，并将确定新的膳食植物补充剂，作为预防太阳紫外线辐射引起的人类皮肤癌的补充方法。预防皮肤癌的危害将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.