Shikonin and Nrf2 Chemoprevention

紫草素和 Nrf2 化学预防

基本信息

批准号：
9031067
负责人：
Qun Zhou
金额：
$ 28.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031067
关键词：
AKT1 gene Antioxidants Binding Breast Cancer Cell Breast Cancer Prevention Breast Cancer Risk Factor Breast Carcinoma Breast Epithelial Cells Carcinogens Chemoprevention Chemopreventive Agent Chemoprotection DNA Damage Development Diet Drug Metabolic Detoxication Enzymes Epithelial Epithelial Cell Proliferation Estrogen Receptor alpha Estrogens Excision Exhibits Exposure to Gene Targeting Genes Genetic Transcription Goals Health Human In Vitro Knock-out Knockout Mice MAPK3 gene Malignant - descriptor Mammary Tumorigenesis Mammary gland Mediating Mediator of activation protein Monitor Mus NF-E2-related factor 2 Nature Oxidoreductase Pathway interactions Plants Production Promoter Regions Proteins Quinones Reactive Oxygen Species Response Elements Role Signal Pathway Signal Transduction Staging Testing Toxic effect Xenograft procedure base breast tumorigenesis carcinogenesis chromatin modification in vivo malignant breast neoplasm malignant state novel novel therapeutics nucleocytoplasmic transport oxidative DNA damage prevent promoter response screening transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Estrogen is a causative factor for the development of breast cancer. It remains critically important to identify novel therapies that prevent estrogen carcinogenesis without significant toxicity. Induction of detoxifying enzymes is considered an important mechanism of protection against estrogen-associated carcinogenesis because they facilitate removal of toxic estrogens. The levels of detoxifying enzymes are determined by the key transcription factor Nrf2 factor that binds to the antioxidant response element in the promoters of genes encoding detoxification enzymes to increase transcription. Thus, a chemoprevention goal is to enhance Nrf2 function. Our preliminary studies show a novel role for shikonin (a bioactive agent extracted from the Shikon plant) in breast cancer prevention via a dual mechanism of action. Shikonin inhibits estrogen signaling and induces Nrf2 expression. This unique chemopreventive activity inhibits transformation from normal mammary epithelial to malignant states and prevents estrogen- dependent tumor formation. Based on these findings, we hypothesize that shikonin activates Nrf2 function leading to increased detoxifying enzyme expression. Consequently, these enzymes will remove genotoxic estrogen, and reduce DNA damage. We will test this hypothesis by determining 1) mechanisms of estrogen and shikonin in regulating expression of Nrf2 and detoxifying enzymes; 2) ability of shikonin to impact the Nrf2-dependent chemoprotection pathway; and 3) the role of Nrf2 in shikonin chemoprevention of mammary tumorigenesis using Nrf2 knockout mice. The results obtained from this proposal reveal that shikonin reverses the estrogen action in a novel way by reducing estrogen suppression of Nrf2 expression. These studies demonstrate that shikonin is a novel dietary agent with great potential as a breast cancer preventative.

描述（由申请人提供）：雌激素是乳腺癌发展的原因。确定防止雌激素致癌而没有明显毒性的新型疗法至关重要。诱导解毒酶被认为是保护雌激素相关的癌变的重要机制，因为它们有助于去除毒性雌激素。解毒酶的水平由关键转录因子NRF2因子确定，该因子与编码解毒酶的基因启动子中的抗氧化反应元件结合以增加转录。因此，化学预防目标是增强NRF2功能。我们的初步研究表明，通过双重作用机理，湿康（Shikonin）（一种从Shikon植物中提取的生物活性剂）在预防乳腺癌中的新作用。 Shikonin抑制雌激素信号传导并诱导NRF2表达。这种独特的化学预防活性抑制了从正常的乳腺上皮变为恶性状态的转化，并防止了雌激素依赖性肿瘤的形成。基于这些发现，我们假设shikonin激活NRF2功能，从而导致酶表达增加。因此，这些酶将去除遗传毒性雌激素并减少DNA损伤。我们将通过确定1）在调节NRF2表达和排毒酶的表达方面的机制来检验这一假设； 2）湿康蛋白影响NRF2依赖性化学保护途径的能力； 3）NRF2在使用NRF2基因敲除小鼠的乳腺肿瘤发生中的作用。从该提案中获得的结果表明，Shikonin通过减少NRF2表达的雌激素抑制来以新颖的方式逆转雌激素作用。这些研究表明，湿康蛋白是一种新型的饮食剂，具有巨大的预防乳腺癌潜力。