Breast cancer prevention with Nexrutine

使用 Nexrutine 预防乳腺癌

• 批准号: 8249801
• 负责人: Susan Patricia Lanza-Jacoby
• 金额: $ 19.18万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249801
• 关键词: Abdominal Pain; Accounting; Address; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Aromatase Inhibitors; Autophagocytosis; Biological Availability; Biological Markers; Botanicals; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Cell Death; Cessation of life; Chemoprevention; China; Chinese Traditional Medicine; Citrus; Clinical Trials; Controlled Clinical Trials; Cyclin D1; Data; Degenerative polyarthritis; Development; Diarrhea; Diet; Dietary Factors; Dinoprostone; Disease; Double-Blind Method; ERBB2 gene; Estrogen Receptors; Estrogen receptor negative; Exploratory/Developmental Grant; Gastroenteritis; Goals; Growth; Herb; Hyperplasia; In Vitro; Incidence; Inflammation; Knowledge; Lesion; MAPK Signaling Pathway Pathway; Magnolia; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maximum Tolerated Dose; Measures; Mediating; Medicinal Plants; Missouri; Molecular; NIH Program Announcements; Nature; Neoplasm Metastasis; New Agents; Outcome; Patients; Phellodendron; Placebo Control; Plants; Postdoctoral Fellow; Premalignant; Prevention; Prevention Protocols; Prevention strategy; Production; Property; Prostatic Neoplasms; Protocols documentation; Raloxifene; Reactive Oxygen Species; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Safety; Serious Adverse Event; Signal Pathway; Signal Transduction; Staging; Tablets; Tamoxifen; Testing; Toxic effect; Transgenic Mice; Trees; United States; Universities; Woman; base; breast cancer diagnosis; breast density; cancer prevention; cancer risk; clinically relevant; cost; design; feeding; human FRAP1 protein; in vivo; killings; malignant breast neoplasm; mouse model; neoplastic cell; nipple aspirate fluid; novel strategies; outcome forecast; preclinical study; prevent; protective effect; public health relevance; response; standard care; tumor

DESCRIPTION (provided by applicant): The prognosis for women with breast tumors that are estrogen receptor (ER)-negative is very poor because these tumors are aggressive and do not respond to standard treatments. This situation emphasizes the importance of developing new agents and protocols for preventing breast cancer. We address this gap of knowledge by examining the effect of Nexrutine, an herbal extract from the Phellodendron amurense plant, on breast cancer incidence and latency with the anticipation of developing this compound as a chemoprevention agent. In support of this study, we found that Nexrutine reduced excessive branching of mammary gland terminal end buds from HER-2/neu transgenic mice and decreased PGE2 production in the mammary glands. These findings suggest that Nexrutine may reduce risk of mammary tumor incidence by altering the early stages of development. Nexrutine also decreased survival of breast cancer cells by inducing cell death, which was associated with autophagy. The role of autophagy in cancer is unclear. This study offers an opportunity to investigate whether autophagy is involved in the prevention of breast cancer. Based upon this preliminary information, we hypothesize that the use of Nexrutine could provide a novel approach to reduce incidence and delay the progression of spontaneous mammary tumors. Additionally, we propose that the protective effects of Nexrutine are associated with induction of autophagy and cell death. We will test this hypothesis by completing the following: AIMS: 1. To determine whether Nexrutine will reduce incidence and multiplicity, and increase tumor latency of spontaneous mammary tumors in HER-2/neu transgenic mice. 2. To investigate mechanisms of Nexrutine-induced autophagic death in tumor cells and tumors from HER-2/neu transgenic mice by defining the Nexrutine-induced autophagic response and determining the role of ERK and Akt/mTOR, and the contribution of reactive oxygen species (ROS) in mediating increase in autophagy in response to Nexrutine treatment. The positive outcome of this preclinical study along with our mechanistic design will provide a strong rationale for establishing a clinical trial to determine the efficacy of Nexrutine as a prevention strategy against breast cancer. The importance of this study resides in the observation that Nexrutine may reduce early biomarkers of breast cancer risk. Completion of the proposed study has high potential of identifying additional biomarkers and signaling pathways to design effective prevention protocols. PUBLIC HEALTH RELEVANCE: Nexrutine is a botanical extract from the Phellodendron amurense tree that is native to Northern China and is one of the top 50 herbs used in traditional Chinese medicine for its anti-inflammatory properities. We have very compelling preliminary data showing that Nexrutine decreases growth of mammary gland terminal end buds and the biomarker, prostaglandin E2 in the HER-2/neu mouse model. Based upon our data showing that Nexrutine has bioavailability, we propose to evaluate the potential of Nexrutine for prevention of precancerous lesions and mammary tumors in a clinically relevant transgenic mouse model. Additionally, our preliminary findings demonstrate that Nexrutine induces autophagy and cell death. Since the role of autophagy in cancer is unclear, we will evaluate whether autophagy is associated with decreased development and incidence of mammary tumors. We also plan to determine mechanisms by which Nexrutine is inducing autophagy by interrogating the role of ERK and Akt/mTOR signaling and reactive oxygen species (ROS) in mediating these effects.

描述（由申请人提供）：患有雌激素受体（ER）阴性乳腺肿瘤的女性的预后非常差，因为这些肿瘤具有侵袭性并且对标准治疗没有反应。这种情况强调了开发新的药物和方案来预防乳腺癌的重要性。我们通过研究 Nexrutine（一种来自黄柏植物的草药提取物）对乳腺癌发病率和潜伏期的影响来解决这一知识空白，并期望将这种化合物开发为化学预防剂。为了支持这项研究，我们发现 Nexrutine 减少了 HER-2/neu 转基因小鼠乳腺末端芽的过度分支，并减少了乳腺中 PGE2 的产生。这些发现表明，Nexrutine 可以通过改变早期发育阶段来降低乳腺肿瘤发生的风险。 Nexrutine 还通过诱导细胞死亡来降低乳腺癌细胞的存活率，这与自噬有关。自噬在癌症中的作用尚不清楚。这项研究提供了一个研究自噬是否参与乳腺癌预防的机会。基于这些初步信息，我们假设 Nexrutine 的使用可以提供一种降低自发性乳腺肿瘤发病率并延缓其进展的新方法。此外，我们认为 Nexrutine 的保护作用与诱导自噬和细胞死亡有关。我们将通过完成以下任务来检验这一假设： 目的： 1. 确定 Nexrutine 是否会降低 HER-2/neu 转基因小鼠中自发性乳腺肿瘤的发病率和多重性，并增加肿瘤潜伏期。 2. 通过定义 Nexrutine 诱导的自噬反应并确定 ERK 和 Akt/mTOR 的作用，以及活性氧 (ROS) 在介导 Nexrutine 治疗响应的自噬增加中的贡献，研究 Nexrutine 诱导 HER-2/neu 转基因小鼠的肿瘤细胞和肿瘤中自噬死亡的机制。这项临床前研究的积极成果以及我们的机制设计将为建立临床试验以确定 Nexrutine 作为乳腺癌预防策略的功效提供强有力的理由。这项研究的重要性在于观察到 Nexrutine 可能会降低乳腺癌风险的早期生物标志物。完成拟议的研究具有识别其他生物标志物和信号通路以设计有效预防方案的巨大潜力。 公共健康相关性：Nexrutine 是黄檗树的植物提取物，黄檗树原产于中国北方，因其抗炎特性而成为中药中使用的 50 种顶级草药之一。我们有非常令人信服的初步数据表明，Nexrutine 可降低 HER-2/neu 小鼠模型中乳腺终末芽和生物标志物前列腺素 E2 的生长。根据我们的数据显示 Nexrutine 具有生物利用度，我们建议在临床相关的转基因小鼠模型中评估 Nexrutine 在预防癌前病变和乳腺肿瘤方面的潜力。此外，我们的初步研究结果表明，Nexrutine 会诱导自噬和细胞死亡。由于自噬在癌症中的作用尚不清楚，我们将评估自噬是否与乳腺肿瘤的发展和发病率下降有关。我们还计划通过探究 ERK 和 Akt/mTOR 信号传导以及活性氧 (ROS) 在介导这些作用中的作用来确定 Nexrutine 诱导自噬的机制。