Breast Cancer Prevention by Ayurvedic Medicine Constituents

阿育吠陀医学成分预防乳腺癌

基本信息

批准号：
8590113
负责人：
Shivendra Singh
金额：
$ 29.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-04 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8590113
关键词：
Adverse effects Animal Model Antioxidants Apoptosis Apoptotic Area Attenuated Ayurvedic Medicine BCL2 gene Bax protein Biological Markers Breast Cancer Cell Breast Cancer Prevention Breast Carcinogenesis Breast Epithelial Cells Cancer Etiology Carcinoma Caspase Cell Death Cell Line Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Trials Data Development Diet Effectiveness Female Future Generations Goals Growth Health Human Hyperplasia Implant Incidence Inhibition of Apoptosis Knowledge Lesion MAPK8 gene MCF10A cells MCF7 cell MDA MB 231 Mammary Neoplasms Mammary Tumorigenesis Mammary gland Maximum Tolerated Dose Mediating Metastatic Neoplasm to the Lung Mitochondria Modeling Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Nude Mice Outcome Oxidation-Reduction Prevention Production Proteins Publishing Reactive Oxygen Species Regimen Regulation Relative (related person)Research Research Project Grants Resistance Role S-Phase Fraction Signal Pathway Signal Transduction Pathway Small Interfering RNA Techniques Testing Thioredoxin Transgenic Mice Tumor Tissue United States Woman Work Xenograft procedure base design genetic regulatory protein glutaredoxin in vivo indexing inhibitor/antagonist insight malignant breast neoplasm mouse model neovascularization novel pre-clinical pre-clinical research prevent public health relevance research study response screening stem stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): Breast cancer continues to be a leading cause of cancer related deaths among women in the United States. The long-term goal of this research project is to develop a safe and effective strategy for prevention of breast cancer in women using a novel Ayurvedic medicine constituent- Withaferin-A (WA). This preclinical research project stems from our published and preliminary unpublished results demonstrating that WA treatment decreases viability of cultured breast cancer cells by causing apoptosis and the proapoptotic effect of WA correlates with generation of reactive oxygen species (ROS), activation of c-Jun- N-terminal kinases (JNK1/2), and induction of proapoptotic proteins Bax, Bak, and Bim. Noticeably, WA administration significantly retards growth of MDA-MB-231 human breast cancer xenografts in female nude mice without causing any harmful side effects. Despite these promising results, however, significant gaps exist in our understanding of the mechanism(s) of WA-induced apoptosis. For example, the precise mechanism of WA-mediated ROS production remains elusive. Likewise, the signaling pathways downstream of ROS production and JNK1/2 activation in execution of WA-induced apoptosis are unclear. Studies proposed in this application will not only fill these mechanistic gaps in our knowledge but also determine in vivo efficacy of WA for prevention of breast cancer in a transgenic mouse model. Based on the results of our preliminary studies, we hypothesize that WA treatment selectively causes ROS/JNK-mediated apoptosis in breast cancer cells leading to chemoprevention of mammary carcinogenesis. Specific Aims: The specific aims of this project are to: (1) Determine the mechanism of WA-mediated ROS production using MDA-MB-231, MCF-7, BRI-JM04, and MCF-10A cell lines as a model; (2) Determine the mechanism of WA-mediated activation of JNK1/2 using the above mentioned cell lines as a model; (3) Determine the signaling pathways downstream of ROS production and JNK1/2 activation in execution of WA- induced apoptosis using above cell lines; the MCF-10A cell line is included in specific aims 1-3 to gain insight into the mechanism of relative resistance of normal mammary epithelial cells towards WA-induced apoptosis; (4) Determine the efficacy of dietary WA administration for prevention of mammary carcinogenesis using MMTV-neu mice; and (5) Determine the mechanism by which dietary WA may prevent breast cancer development in MMTV-neu mice using mammary tumor tissues from control and WA-treated MMTV-neu mice. Significance of the Proposed Research: Positive outcome of the proposed preclinical in vivo efficacy study will provide impetus for clinical trials to determine chemopreventive effectiveness of WA against human breast cancer. The value of defining the mechanism of anticancer effect of WA may be realized in a variety of ways including identification of biomarker(s) of WA response potentially useful in future clinical trials and optimization of WA-based chemopreventive regimens against breast cancer.

描述（由申请人提供）：乳腺癌仍然是美国女性癌症与癌症相关的主要原因。该研究项目的长期目标是制定一种安全有效的策略，以使用一种新型的印度草药医学组成 - 伴有AFERIN-A（WA）来预防妇女的乳腺癌。 This preclinical research project stems from our published and preliminary unpublished results demonstrating that WA treatment decreases viability of cultured breast cancer cells by causing apoptosis and the proapoptotic effect of WA correlates with generation of reactive oxygen species (ROS), activation of c-Jun- N-terminal kinases (JNK1/2), and induction of proapoptotic proteins Bax, Bak, and Bim.明显的是，西澳大利亚州的给药显着降低了雌性裸鼠中MDA-MB-231人类乳腺癌异种移植物的生长，而不会引起任何有害的副作用。尽管有这些有希望的结果，但是在我们对WA诱导的凋亡机制的理解中仍然存在明显的差距。例如，WA介导的ROS产生的确切机制仍然难以捉摸。同样，在WA诱导的凋亡执行中，ROS产生和JNK1/2激活的信号传导途径尚不清楚。本应用中提出的研究不仅会在我们的知识中填补这些机械差距，而且还可以确定WA在转基因小鼠模型中预防乳腺癌的体内功效。根据我们的初步研究的结果，我们假设WA治疗有选择地引起ROS/JNK介导的乳腺癌细胞中的凋亡，从而导致乳腺癌化学预防。具体目的：该项目的具体目的是：（1）使用MDA-MB-231，MCF-7，BRI-JM04和MCF-10A细胞系确定WA介导的ROS产生的机理；（2）使用上述细胞系作为模型来确定WA介导的JNK1/2激活的机理；（3）确定ROS产生的信号传导途径和使用上述细胞系在执行WA诱导的凋亡时的JNK1/2激活； MCF-10A细胞系包含在特定目标1-3中，以深入了解正常乳腺上皮细胞对WA诱导凋亡的相对耐药性的机理；（4）确定使用MMTV-NEU小鼠饮食中WA给药预防乳腺癌的功效；（5）确定使用对照和WA处理的MMTV-NEU小鼠使用乳腺肿瘤组织的MMTV-NEU小鼠乳腺癌在MMTV-NEU小鼠中的发展机制。拟议研究的重要性：拟议的临床前体内疗效研究的积极结果将为临床试验提供动力，以确定WA对人类乳腺癌的化学预防有效性。定义WA抗癌作用机理的价值可以通过多种方式实现，包括鉴定WA反应的生物标志物在将来的临床试验中有可能有用，并优化了对乳腺癌的基于WA的化学预防治疗方案。