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

• 批准号: 8240040
• 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
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240040
• 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; public health relevance; reaction rate; silibinin; skin cancer prevention; transcription factor; tumorigenesis

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(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质，反复暴露会导致黑色素瘤和非黑色素瘤皮肤癌的发展。除了防晒霜外，建议使用天然无毒化合物化学预防皮肤癌，作为预防皮肤癌的有效策略。我们在体外和体内对黑莓和其他食物中发现的化合物氰基-3-葡萄糖苷(C3G)的研究表明，该化合物能够抑制HL60细胞中NF-B、AP-1、COX2和TNF1的激活/表达、肿瘤转化、癌细胞迁移和侵袭，以及诱导细胞凋亡。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而发挥抗氧化剂的作用。这些初步研究表明，C3G可能是一种潜在的化学预防和化疗药物。这一应用的总体假设是，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诱导的致癌。具体目的1.C3G的体内外抗氧化性能研究。在非细胞体系中，利用Fenton反应(Fe(II)+H_2O_2)和黄嘌呤/黄嘌呤氧化酶作为这些自由基的来源，用电子自旋共振(ESR)自旋捕获法测定C3G对羟基(7OH)和超氧阴离子(O_(27-))自由基的反应速率，并研究细胞体系中对UVB诱导的7OH和O_(27-)自由基的抗氧化活性。低频(体内)ESR也将被用于研究C3G对UVB产生的SKH-1无毛小鼠皮肤中的O27-和7OH自由基的抗氧化活性。具体目的2.体内研究C3G对UVB诱导的氧化应激及氧化应激敏感转录因子激活的影响。我们将研究C3G对UVB诱导的KSH小鼠脂质过氧化、蛋白质氧化和DNA氧化损伤的影响。我们还将研究C3G对UVB诱导的转基因小鼠激活蛋白(AP)-1、核因子(NF)-B和活化T细胞核因子(Naft)的激活的影响。具体目的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性白细胞和髓过氧化物酶(MPO)、COX-2、PGE2，以及几种促炎细胞因子，如肿瘤坏死因子-1、白介素2和白介素6。具体目的4.研究C3G在UVB诱导的肿瘤发生和早期生物标志物中的作用。这些标记物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预防皮肤癌的早期疗效提供机制基础。 公共卫生相关性：紫外线诱发皮肤癌的发病率是一个主要的公共卫生问题。本研究试图确定氰基-3-葡萄糖苷是一种植物来源的化合物，是一种基于机制的预防紫外线诱发皮肤癌的药物。