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

描述（由申请人提供）：天然植物产品作为抗癌药物的新来源的重要性日益明显。使用天然植物衍生产品的好处是它们的低毒性、多模式作用和增强免疫系统的潜在能力。随着分析技术的进步，我们可以分析这些化合物的活性成分的活性，这些活性成分专门针对癌细胞中的生物途径。Withaferin A （WA）是Withania somnifera（俗称Ashwagandha）的纯化产品，作为印度阿育吠陀医学的一部分，许多世纪以来一直用于许多土著药物制剂中。白藜芦醇已被证明具有有效的抗癌特性，并可靶向多种导致肿瘤细胞凋亡的细胞通路

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.