Enhancing NK Cell Activity by Dietary Diphyllin Lignans for Cancer Prevention

描述（由申请人提供）：膳食成分已成为非常有吸引力的癌症预防剂。为此，我们设想使用饮食成分来调节先天免疫细胞功能，以预防癌症。调节自然杀伤细胞（NK）可以治疗急性髓性白血病（AML），并且NK细胞活性与AML的无复发生存率相关。AML是一种主要影响老年人的疾病：诊断时的中位年龄超过65岁，5年生存率仍低于10%。老年AML患者较难耐受对年轻患者有效的治疗，如强化化疗和同种异体干细胞移植。因此，新的、毒性更小的预防AML和AML复发的方法代表了尚未满足的治疗需求。初步研究表明，从食用植物中分离得到的一种叶香素（phyllanthusmin C, plc）具有增强NK细胞活性的作用。PL-C通过上调NF-kB信号组件p65来增强人NK细胞干扰素γ (IFN-γ)的产生。这一发现与我们的体内数据一致，表明在我们的同基因原位动物模型中，用PL-C治疗可以延长患有AML的小鼠的存活时间。我们还发现，口服给药200 mg/kg后30分钟可在小鼠血浆中检测到PL-C。基于这些数据，我们推测来自可食用植物的PL-C可以增强NK细胞的杀瘤活性，从而可能具有预防包括AML在内的癌症的治疗功效。我们提出通过以下三个目的来验证我们的假设：目的1是确定PL-C是否在体外调节NK细胞对AML细胞的细胞毒性；目的2：探讨PL-C增强NK细胞抗肿瘤活性的机制。目的3：研究PL-C在体内预防AML的临床前疗效。据我们所知，这是第一次从可食用植物中提取的木脂素为基础的膳食成分被证明能够特异性和显著地增强人类NK细胞的功能。因此，我们的研究可能为癌症预防开辟一条新的途径。由于PL-C是一种来自可食用植物的化合物，因此这项临床前研究具有相对较强的潜力，可以转化为临床I期、II期和III期化学预防试验，这些试验将在研究完成后启动

DESCRIPTION (provided by applicant): Dietary components have become very attractive agents for cancer prevention. Toward this end, we envision the use of dietary components to modulate innate immune cell function with the goal of cancer prevention. Natural killer (NK) cells can be modulated to cure acute myeloid leukemia (AML), and NK cell activity is correlated with relapse-free survival in AML. AML is a disease that primarily affects older adults: the median age at diagnosis is over 65, and the 5-year survival rate remains under 10%. Elderly AML patients are less able to tolerate therapies effective in younger patients, such as intensive chemotherapy and allogeneic stem cell transplantation. Therefore, novel, less toxic, approaches to prevent AML and AML relapse represent an unmet therapeutic need. Our preliminary data show that phyllanthusmin C (PL-C), a diphyllin lignan isolated from edible plants, can enhance NK cell activity. PL-C enhances human NK cell interferon-gamma (IFN-γ) production via upregulation of the NF-kB signaling component, p65. This finding is consistent with our in vivo data, showing that treatment with PL-C can prolong the survival of the mice bearing AML in our syngeneic orthotopic animal model. We also found that PL-C can be detected in murine plasma 30 minutes after administration via oral gavage at a dose of 200 mg/kg. Based on these data, we hypothesize that PL-C originated from edible plants can enhance NK cell tumoricidal activity, and thus may possess therapeutic efficacy in the prevention of cancers including AML. We propose to test our hypothesis through the following three Aims: Aim 1 is to determine whether PL-C regulates NK cell cytotoxicity against AML cells in vitro; Aim 2 is to investigate the mechanisms by which PL-C enhances NK cell anti-tumor activity. Aim 3 is to study the preclinical efficacy of PL-C in the prevention of AML in vivo. To our knowledge, this is the first time that a lignan-based dietary component from an edible plant has been demonstrated to specifically and significantly enhance human NK cell function. As such, our study may open a new avenue for cancer prevention. Because PL-C is a compound that comes from an edible plant, this preclinical study has relatively strong potential for translation into the clinic as Phse I, Phase II, and then Phase III chemoprevention trials to be initiated following completion of this study. Therefore, not only is our study innovative and significant, but it is also highly translational.