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

描述(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。使用天然植物来源的产品的好处是它们的低毒、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(Withaferin A，WithaferWa显示了强大的抗癌特性，并针对多种细胞途径，通过多种途径导致肿瘤细胞的凋亡。 机械装置。最近，它被证明通过抑制HSP90(oh等人，2009)以及通过上调人肾癌细胞中的内质网应激蛋白(Choi等人，2011)来促进人胰腺癌细胞的凋亡。此外，研究还证明，母植物的粗根和叶提取物通过上调细胞因子，如干扰素-γ，诱导抗原提呈细胞上的共刺激分子，以及促进T细胞的增殖来刺激辅助性T细胞1型(Th1)免疫(Malik等人，2009，Stan等人，2009)。然而，关于全身给药影响肿瘤特异性免疫的机制尚不清楚。我们的初步数据表明，WA导致细胞死亡，并以剂量依赖的方式诱导免疫刺激蛋白如热休克蛋白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免疫和细胞免疫在免疫系统中发挥重要作用。基于这些结果，我们认为WA可以通过激活树突状细胞(DC)等天然免疫细胞和随后刺激获得性免疫来激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，本研究的应用将集中在两个目标上：a)经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在小鼠临床前模型(可移植模型和HER-2/neu转基因模型)中对肿瘤延迟和存活的影响，包括WA是否能特异性靶向HER-2/neu肿瘤特异性免疫。我们的目标是建立和提供证据，证明天然产品，如Withaferin A，可以作为化学免疫治疗剂用于治疗HER-2/neu乳腺癌。这种策略的好处将影响休眠肿瘤细胞在常规化疗方案后频繁复发的转移，这可能会导致肿瘤复发和治疗失败。

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.