Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside

花青素-3-葡萄糖苷预防紫外线诱发的致癌作用

基本信息

批准号：
8133594
负责人：
Xianglin Shi
金额：
$ 33.41万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133594
关键词：
Acetates Animal Model Anthocyanins Anthracenes Antioxidants Apoptosis Apoptotic Berry Biological Markers Cabbage - dietary Cells Chemicals Chemoprevention Chemopreventive Agent Chronic Chronic Disease Clinical Research Complement Factor B Consumption DNA Nucleotidylexotransferase Development Diet Dinoprostone EGF gene Electron Spin Resonance Spectroscopy Environmental Carcinogens Enzymes Epidemiologic Studies Epidermis Epigallocatechin Gallate Exhibits Family Food Free Radicals Frequencies Generations Glucosides Grapes Green tea Growth Factor HL-60 Cells Human Hydrogen Peroxide Hydroxyl Radical In Vitro Inbred HRS Mice Incidence Individual Induction of Apoptosis Inflammation Inflammation Mediators Inflammatory Interleukin-2 Interleukin-6 Investigation Label Laboratories Laboratory Study Lead Leukocytes Link Lipid Peroxidation MAP Kinase Gene Malignant Neoplasms Mediating Mediator of activation protein Methods Micronutrients Milk Thistle Minerals Mus Neoplastic Cell Transformation Non-Malignant Nuclear Nuclear Antigens Oxidative Stress PTGS2 gene Peroxidases Phytochemical Pigments Plants Population Prevention Preventive Property Prostaglandins Proteins Public Health Reaction Reactive Oxygen Species Signal Pathway Signaling Protein Skin Skin Cancer Skin Carcinoma Source Spin Trapping Stimulus Sunlight Sunscreening Agents Superoxides System TNF gene Therapeutic Thymine Topical application Transgenic Mice Tumor Necrosis Factor-alpha UVB induced Ultraviolet B Radiation Ultraviolet Rays Vitamins Xanthine Oxidase Xanthines ascorbate base cancer cell carcinogenesis cell motility cell transformation chemotherapeutic agent cyclooxygenase 2 cytokine fruits and vegetables high risk in vivo melanoma member nuclear factor 1 nuclear factors of activated T-cells oxidation oxidative DNA damage prevent protein activation reaction rate silibinin skin cancer prevention transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Epidemiological, clinical, and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens, chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G), a compound found in blackberries and other foods, show that this compound is able to inhibit NF-:B, AP-1, COX2, and TNF1 activation/expression, neoplastic transformation, cancer cell migration and invasion, and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress, activation of transcription factors, and inflammatory signaling proteins, leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals, using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system, and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation, protein oxidation, and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1, nuclear factor (NF)-:B, and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO), COX-2, PGE2, and several pro-inflammatory cytokines, TNF-1, IL-2, and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells, proliferative cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention. PUBLIC HEALTH RELEVANCE: The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside, a plant-derived compound, as a mechanism-based preventive agent against UV-induced skin cancers.

描述（由申请人提供）：流行病学、临床和实验室研究表明，紫外线辐射 (UV) 是一种完全的环境致癌物，反复接触可导致黑色素瘤和非黑色素瘤皮肤癌的发生。除了防晒霜之外，还建议通过天然无毒化合物对皮肤癌进行化学预防，作为预防皮肤癌发病的有效策略。我们对花青素-3-葡萄糖苷 (C3G)（一种存在于黑莓和其他食品中的化合物）的体外和体内研究表明，该化合物能够抑制 NF-:B、AP-1、COX2 和 TNF1 激活/表达、肿瘤转化、癌细胞迁移和侵袭以及诱导 HL60 细胞凋亡。 C3G 还通过抑制活性氧的产生和诱导抗氧化剂调节转录因子发挥抗氧化剂的作用。这些初步研究表明，C3G 可能作为一种潜在的化学预防和化疗剂。该应用的总体假设是，C3G 作为抗氧化剂发挥作用，抑制氧化应激、转录因子的激活和炎症信号蛋白，从而防止 UVB 诱导的癌变。具体目标 1. C3G 抗氧化特性的体外和体内研究。电子自旋共振 (ESR) 自旋捕获将用于确定 C3G 对羟基 (7OH) 和超氧化物 (O27-) 自由基的反应速率，使用芬顿反应 (Fe(II) + H2O2) 和黄嘌呤/黄嘌呤氧化酶作为来源这些自由基在非细胞系统中的存在，并研究细胞系统中针对 UVB 诱导的 7OH 和 O27- 自由基的抗氧化活性。低频（体内）ESR 还将用于研究 C3G 对 SKH-1 无毛小鼠皮肤中 UVB 产生的 O27- 和 7OH 自由基的抗氧化活性。具体目标2.体内研究C3G对UVB诱导的氧化应激和氧化应激敏感转录因子激活的影响。我们将研究 C3G 对 KSH 小鼠中 UVB 诱导的脂质过氧化、蛋白质氧化和氧化性 DNA 损伤的影响。我们还将在转基因小鼠中研究 C3G 对 UVB 诱导的激活蛋白 (AP)-1、核因子 (NF)-:B 和激活 T 细胞核因子 (NAFT) 激活的影响。具体目标 3. 研究 C3G 对 UVB 诱导的炎症介质的影响。这些炎症介质包括浸润白细胞和髓过氧化物酶 (MPO)、COX-2、PGE2 和几种促炎细胞因子、TNF-1、IL-2 和 IL-6。具体目标 4. 研究 C3G 对 UVB 诱导的肿瘤发生和早期生物标志物的影响。这些标记包括胸腺嘧啶阳性细胞、增殖细胞核抗原、末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记、凋亡细胞以及表皮中 p53 和 p21/cip1 阳性细胞群的变化。这些研究将为 C3G 预防皮肤癌的早期功效提供机制原理。公共健康相关性：紫外线诱发的皮肤癌的发病率是一个主要的公共健康问题。目前的研究试图确定矢车菊素-3-葡萄糖苷（一种植物源性化合物）作为基于机制的预防剂，预防紫外线诱发的皮肤癌。