Immunomodulatory Mechanisms of Withafarin A in Her-2 neu breast cancer

Withafarin A 对 Her-2 neu 乳腺癌的免疫调节机制

基本信息

批准号：
8400815
负责人：
ANNALISE ROXANNE SMITH
金额：
$ 2.88万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/8400815
关键词：
Antibodies Antigen-Presenting Cells Antineoplastic Agents Apoptosis Ashwagandha Ayurvedic Medicine B-Lymphocytes Biological Biological Assay Biological Factors Bone Marrow Breast Cancer Cell CD40 Antigens Cancer Etiology Cancer Model Cancer Patient Cell Culture Techniques Cell Death Cells Cellular Immunity Cessation of life Chemotherapy-Oncologic Procedure Clinical Trials Cytotoxic T-Lymphocytes Data Dendritic Cells Diet Disease Dose Drug Compounding Drug resistance ERBB2 gene Failure Goals Growth and Development function HSP 90 inhibition Heat shock proteins Heat-Shock Proteins 70 Human Humoral Immunities Immune Immune response Immune system Immunity Immunotherapeutic agent In Vitro Indigenous Interferon Type II Malignant Neoplasms Mediating Medicinal Plants Methodology Molecular Molecular Chaperones Mus National Center for Complementary and Alternative Medicine Natural Immunity Neoplasm Metastasis Oncogenic Parents Pathway interactions Pharmaceutical Preparations Plant Leaves Plant Roots Plants Play Pre-Clinical Model Property Proteins Rattus Recurrence Relapse Renal Cell Carcinoma Research Role Route Source Surface T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing Therapeutic Toxic effect Transgenic Model Transgenic Organisms Tumor Antigens United States Up-Regulation Withania somnifera Woman Work adaptive immunity base biological adaptation to stress cancer cell cancer therapy cancer type cell growth cellular targeting chemotherapy combat cytokine immunogenic improved in vivo macrophage malignant breast neoplasm mouse model neoplastic cell novel outcome forecast overexpression pancreatic cancer cells response stress protein tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The importance of natural plant products as novel sources of anticancer agents is increasingly becoming evident. The benefit of using natural plant derived products is their low toxicity, multimodal action and their potential ability to enhance the immune system. With the advancement of analytical techniques we can analyze the activity of active components of these compounds that specifically target biological pathways in the cancer cell. Withaferin A (WA) is a purified product of Withania somnifera, (commonly known as Ashwagandha) and is used in many indigenous drug preparations as part of Indian ayurvedic medicine for many centuries. WA has demonstrated potent anti- cancer properties and targets several cellular pathways that result in apoptosis of tumor cells by various mechanisms. Recently it was shown to potentiate apoptosis of human pancreatic cancer cells through inhibition of HSP90 (Oh et al., 2009) as well as through up-regulation of ER stress proteins in human renal carcinoma cells (Choi et al., 2011). Additionally, it was demonstrated that crude root and leaf extracts from the parent plant stimulates T helper Type 1 (Th1) immunity by up-regulation of cytokines such as interferon gamma, induction of co-stimulatory molecules on antigen presenting cells and increased proliferation of T cells (Malik et al., 2009, Stan et al., 2009). However, nothing has been established about the mechanisms by which systemic administration of WA impacts tumor specific immunity. Our preliminary data indicates that WA causes cell death and also induces the expression of immunostimulatory proteins such as heat shock protein 70 (HSP70) in a dose dependent fashion. Expression of HSP70 in the tumor cells plays a fundamental role in the immune system by inducing tumor specific humoral and cellular immunity. Based on these results, we propose that WA can stimulate an immune mediated cancer cell death by eliciting tumor specific response by the host, through activation of innate immune cells such as dendritic cells (DCs) and subsequent stimulation of adaptive immunity. This research application will therefore focus on two goals: a) effect of WA treated tumor cells on innate immunity: dendritic cells and macrophages and b) effect of WA in tumor delay and survival in murine preclinical models (transplantable and Her-2/neu transgenic models) including whether WA can specifically target Her-2/neu tumor specific immunity. Our goal is to establish and provide evidence that natural products such as Withaferin A can be used as a chemoimmunotherapeutic agent in the treatment of Her-2/neu breast cancers. The benefit of such a strategy would impact the frequent recurrence of metastases of dormant tumor cells after conventional chemotherapy regimens that can cause tumor relapse and therapeutic failure. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women in the United States and thirty percent of breast cancers overexpress Her-2/neu oncogenic protein, which correlate with poor prognosis. The focus of this application is to develop novel agents that can deliver multimodal action in cancer cell death. We propose to utilize a natural plant product Withaferin A (WA) derived from the Indian ayurvedic medicinal plant Withania somnifera for treating Her-2/neu cancer.

描述（由申请人提供）：天然植物产品作为抗癌剂的新来源的重要性越来越明显。使用天然植物衍生产品的好处是它们的低毒性，多模式作用及其增强免疫系统的潜在能力。随着分析技术的发展，我们可以分析这些化合物的活性成分的活性，这些化合物专门针对癌细胞中的生物途径。 withaferin a（WA）是Withania Somnifera（通常称为Ashwagandha）的纯化产物，并且在许多本地药物制剂中被用作印度阿育吠陀医学的一部分。 WA已显示出有效的抗癌特性，并针对几种细胞途径，这些途径导致各种肿瘤细胞凋亡机制。最近，通过抑制HSP90（OH等，2009）以及通过在人肾脏癌细胞中的ER应激蛋白上调（Choi等，2011），它显示出可以增强人胰腺癌细胞的凋亡。此外，事实证明，来自母体植物的粗根和叶提取物通过上调诸如干扰素伽马等细胞因子的上调，诱导抗原呈现细胞的共刺激分子和增加T细胞的增殖而刺激T辅助型1（Th1）免疫（Malik等，2009，2009，Stan等，2009）。但是，关于WA的系统给药影响肿瘤特异性免疫的机制尚未确定。我们的初步数据表明，WA会导致细胞死亡，并以剂量依赖性方式诱导免疫刺激蛋白（例如热休克蛋白70（HSP70））的表达。 Hsp70在肿瘤细胞中的表达通过诱导肿瘤特异性的体液和细胞免疫来在免疫系统中起基本作用。基于这些结果，我们建议WA可以通过激活先天免疫细胞（例如树突状细胞（DC））以及随后刺激适应性免疫来刺激免疫介导的癌细胞死亡。因此，该研究应用将侧重于两个目标：a）WA处理过的肿瘤细胞对先天免疫的影响：树突状细胞和巨噬细胞以及b）WA在鼠临床前模型（包括移植和HER-2/NEU转基因模型）中WA在肿瘤延迟和存活中的影响，包括WA是否可以具体靶向Her-2/Neuu肿瘤特异性靶向HER-2/NEU肿瘤特异性。我们的目标是建立并提供证据，表明诸如withaferin a之类的天然产品可以用作HER-2/NEU乳腺癌治疗的化学免疫治疗剂。这种策略的益处将影响常规化学疗法治疗方案后休眠肿瘤细胞转移的频繁复发，该方案可能导致肿瘤复发和治疗衰竭。公共卫生相关性：乳腺癌是美国女性癌症死亡的第二大主要原因，而乳腺癌的三十％过表达HER-2/NEU致癌蛋白，这与预后不良有关。该应用的重点是开发可以在癌细胞死亡中提供多模式作用的新型药物。我们建议使用源自印度阿育吠陀药用植物withania somnifera的天然植物产品（WA）来治疗HER-2/NEU癌。