Apple peel extract inhibits Cr(VI)-induced lung cancer

苹果皮提取物抑制 Cr(VI) 诱导的肺癌

• 批准号: 8401004
• 负责人: Zhuo Zhang
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401004
• 关键词: Acetates; Animal Model; Animals; Antioxidants; Apple; Benz(a)Anthracenes; California; Carcinogens; Cell Proliferation; Chemopreventive Agent; Chromium; Chronic; Chronic Disease; Complex; Consumption; Data; Development; Diet; Electron Spin Resonance Spectroscopy; Environmental Carcinogens; Epidemiologic Studies; Equilibrium; Exposure to; Female; Free Radicals; Frequencies; Fruit; Generations; Glutathione Reductase; Goals; Human; Hydrogen Peroxide; Hydroxyl Radical; Inbred BALB C Mice; Incidence; Inflammation; Inflammatory; Inhalation Exposure; Injury; International Agency for Research on Cancer; Investigation; Life; Lung Inflammation; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Molecular; Mus; NADP; NADPH Oxidase; Non-Malignant; Nose; Occupational; Occupational Groups; Oral; Oral Administration; Oxidative Stress; Oxygen; Phytochemical; Plants; Play; Podophyllum peltatum; Process; Protective Agents; Proteins; Radial; Reaction; Reactive Oxygen Species; Reducing Agents; Role; Skin; Skin Cancer; Source; Structure; Structure of parenchyma of lung; Superoxides; System; TNF gene; Tissues; Water; benzanthracene; carcinogenesis; carcinogenicity; chelation; in vivo; instrument; lung injury; tumorigenesis

DESCRIPTION (provided by applicant): Cr(VI)-containing compounds are well established environmental carcinogens. Although the mechanisms of Cr(VI) carcinogenesis remain to be investigated, various studies indicate that Cr(VI)-induced generation of reactive oxygen species (ROS) plays a key role. Many naturally occurring substances present in the human diet have been identified as potential chemopreventive agents. Investigations using animal models and epidemiological studies indicate that consumption of phytochemicals might reduce the incidence of cancers and other chronic diseases. These plant-derived phytochemicals are rich sources of naturally occurring antioxidants. Our preliminary studies have shown that oral administration of apple peel extract decreased the number of nonmalignant and malignant skin tumors induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7, 12-dimethyl Benz (a) anthracene-initiated mouse skin. Apple peel extract is able to directly scavenge hydroxyl radial (OH) and superoxide radical (O2-). Our preliminary studies have also shown that apple peel extract inhibited Cr(VI)-induced "OH radical generation in cellular system. The mechanisms involve direct scavenging of OH radical and chelation of Cr(V) by apple peel extract to make this chromium intermediate less reactive toward hydrogen peroxide(H2O2) for OH radical generation. Our preliminary data have shown that apple peel extract inhibited Cr(VI)-induced expressions of inflammatory proteins including NF-?B and TNF-¿. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against Cr(VI)-induced lung cancer via inhibition of Cr(VI)-induced oxidative stress. Aim 1 will use in vivo electron spin resonance (ESR) to investigate inhibition of Cr(VI)-generated free radicals by apple peel extract in living animals (BALB/c mice). Two approaches will be used: (a) to investigate the chelation of Cr(V)-NADPH complex or change of its structure by apple peel extract; and (b) to investigate the inhibition of apple peel extract on Cr(VI)-induced free radical generation. Aim 2 will investigate the protection of apple peel extract against Cr(VI)-induced lung inflammation, chronic oxidative lung tissue injury, and cell proliferation using BALB/c mice. There are increasing studies supporting the association among oxidative stress, chronic inflammation, and cancer development. Because oxidative stress plays an important role in inflammation, cell proliferation, and tissue injury, itis likely that inhibition of oxidative stress will protect Cr(VI)-induced chronic lung injury and an inflammatory microenvironment, leading to the protection in Cr(VI)-induced lung cancer. In this aim we will Investigate the protection of apple peel extract against Cr(VI)-induced inflammation, chronic oxidative lung injury, and cell proliferation using female BALB/c mice. PUBLIC HEALTH RELEVANCE: The Cr(VI)-containing compounds are well established environmental carcinogens. Oxidative stress is considered to play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The goal of this proposal is to develop apple peel extract as an antioxidant and a protective agent against Cr(VI)-induced oxidative stress and lung cancer.

描述（由申请人提供）：含 Cr(VI) 的化合物是公认的环境致癌物，尽管 Cr(VI) 致癌的机制仍有待研究，但各种研究表明 Cr(VI) 会诱导活性氧的产生。人类饮食中存在的许多天然物质已被确定为潜在的化学预防剂，动物模型和流行病学研究表明，摄入植物化学物质可能会降低癌症的发病率。我们的初步研究表明，口服苹果皮提取物可减少 12-O-tetradecanolyphorbol-13- 诱发的非恶性和恶性皮肤肿瘤的数量。 7, 12-二甲基苯(a)蒽引发的小鼠皮肤中的乙酸酯(TPA)能够直接清除羟基。我们的初步研究还表明，苹果皮提取物可抑制细胞系统中 Cr(VI) 诱导的“OH 自由基”的产生。其机制包括直接清除 OH 自由基和螯合 Cr()。 V) 通过苹果皮提取物降低这种铬中间体对过氧化氢 (H2O2) 产生 OH 自由基的反应性。我们的初步数据表明，苹果皮提取物可抑制 Cr(VI) 诱导的炎症蛋白表达。包括 NF-?B 和 TNF-¿我们研究苹果皮提取物可以作为抗氧化剂，并通过抑制 Cr(VI) 诱导的氧化应激来作为针对 Cr(VI) 诱导的肺癌的化学预防剂。研究苹果皮提取物对活体动物（BALB/c 小鼠）产生的自由基的抑制作用：（a）研究 Cr(V)-NADPH 的螯合作用。苹果皮提取物复合或改变其结构；以及（b）研究苹果皮提取物对 Cr(VI) 诱导的自由基生成的抑制作用，目的 2 将研究其保护作用。 越来越多的研究支持氧化应激、慢性炎症和癌症发展之间的关联。在炎症、细胞增殖和组织损伤中发挥重要作用，氧化应激的抑制很可能会保护 Cr(VI) 诱导的慢性肺损伤和炎症微环境，从而对 Cr(VI) 诱导的慢性肺损伤和炎症微环境产生保护作用。为此，我们将使用雌性 BALB/c 小鼠研究苹果皮提取物对 Cr(VI) 诱导的炎症、慢性氧化性肺损伤和细胞增殖的保护作用。 公共健康相关性：含 Cr(VI) 化合物是公认的环境致癌物，氧化应激被认为在 Cr(VI) 诱发的致癌机制中发挥着重要作用。该提案的目标是开发苹果皮提取物。作为抗氧化剂和针对 Cr(VI) 诱导的氧化应激和肺癌的保护剂。