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：
8540089
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/8540089
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.

描述（由申请人提供）：天然植物产品作为抗癌剂新来源的重要性日益变得明显。使用天然植物衍生产品的好处是其低毒性、多模式作用以及增强免疫系统的潜在能力。随着分析技术的进步，我们可以分析这些专门针对癌细胞生物途径的化合物的活性成分的活性。睡茄素 A (WA) 是睡茄（俗称 Ashwagandha）的纯化产品，几个世纪以来一直作为印度阿育吠陀医学的一部分用于许多本土药物制剂中。 WA 已证明具有强大的抗癌特性，并针对多种细胞途径，通过多种途径导致肿瘤细胞凋亡。机制。最近，它被证明可以通过抑制 HSP90（Oh 等人，2009）以及通过上调人肾癌细胞中的 ER 应激蛋白（Choi 等人，2011）来增强人胰腺癌细胞的凋亡。此外，研究还表明，母本植物的粗根和叶提取物可通过上调干扰素 γ 等细胞因子、诱导抗原呈递细胞上的共刺激分子以及增加 T 辅助细胞增殖来刺激 1 型辅助 T (Th1) 免疫力。细胞（Malik 等人，2009；Stan 等人，2009）。然而，全身给药 WA 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体液和细胞免疫在免疫系统中发挥重要作用。基于这些结果，我们提出WA可以通过激活树突状细胞（DC）等先天免疫细胞并随后刺激适应性免疫，引发宿主的肿瘤特异性反应，从而刺激免疫介导的癌细胞死亡。因此，本研究应用将重点关注两个目标：a) WA 处理的肿瘤细胞对先天免疫的影响：树突状细胞和巨噬细胞，b) WA 对小鼠临床前模型（可移植和 Her-2/neu 转基因）中肿瘤延迟和存活的影响模型），包括 WA 是否可以特异性针对 Her-2/neu 肿瘤特异性免疫。我们的目标是建立并提供证据证明 Withaferin A 等天然产物可用作治疗 Her-2/neu 乳腺癌的化学免疫治疗剂。这种策略的好处将影响常规化疗方案后休眠肿瘤细胞转移的频繁复发，这可能导致肿瘤复发和治疗失败。