Enhancing NK Cell Activity by Dietary Diphyllin Lignans for Cancer Prevention

通过膳食二茶碱木脂素增强 NK 细胞活性以预防癌症

• 批准号: 8818721
• 负责人: MICHAEL A CALIGIURI
• 金额: $ 35.23万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-18 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818721
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Age; Age-Years; Allogenic; Animal Model; Antibodies; Antigen Receptors; Area; Berry; Beverages; Biological Factors; CBL gene; Cell Therapy; Cell physiology; Cells; Chemoprevention; Chronic Lymphocytic Leukemia; Clinic; Curcumin; Cytolysis; Data; Development; Diagnosis; Diet; Dietary Component; Dietary intake; Disease; Dose; Edible Plants; Elderly; Ellagic Acid; Epigenetic Process; Genetic; Glioblastoma; Goals; Health; Human; Immune; Immune Targeting; In Vitro; Induction of Apoptosis; Interferon Type II; Large granular lymphocyte; Lignans; Liquid substance; Literature; Malignant Neoplasms; Modification; Multiple Myeloma; Mus; Mutate; NF-kappa B; Natural Killer Cells; Neoplasm Metastasis; Normal Cell; Oral; Patients; Phase; Phyllanthus; Plant Roots; Plasma; Play; Population Study; Premalignant; Prevention; Primary Neoplasm; Production; Relapse; Research; Role; Shapes; Signal Transduction; Solid Neoplasm; Source; Stem cell transplant; Survival Rate; Testing; Therapeutic; Therapeutic Human Experimentation; Time; Tissues; Translations; Treatment Efficacy; Tumor Antigens; Up-Regulation; Water; base; cancer prevention; cancer risk; cancer therapy; chemotherapy; circulating microRNA; cytokine; cytotoxicity; effective therapy; follow-up; immunogenicity; in vivo; innovation; killer immunoglobulin-like receptor; malignant breast neoplasm; neoplastic cell; novel; older patient; p65; peripheral blood; pre-clinical research; preclinical efficacy; preclinical study; prevent; tumor; ubiquitin ligase

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.

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，我们设想使用膳食成分来调节先天免疫细胞功能，以达到预防癌症的目标。自然杀伤（NK）细胞可以被调节以治愈急性髓性白血病（AML），并且NK细胞活性与AML的无复发生存期相关。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年生存率低于10%。老年AML患者对年轻患者有效的治疗耐受性较差，如强化化疗和异基因干细胞移植。因此，预防AML和AML复发的新的、毒性较小的方法代表了未满足的治疗需求。我们的初步数据表明，叶下珠素C（PL-C），从食用植物中分离的diphyllin木脂素，可以增强NK细胞活性。PL-C通过上调NF-kB信号传导组分p65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治疗可以延长携带AML的小鼠的存活。我们还发现，在以200 mg/kg的剂量经口灌胃给药后30分钟，可在鼠血浆中检测到PL-C。基于这些数据，我们假设来源于可食用植物的PL-C可以增强NK细胞的杀肿瘤活性，因此可能在预防包括AML在内的癌症方面具有治疗功效。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是研究PL-C增强NK细胞抗肿瘤活性的机制。目的3是研究PL-C在体内预防AML的临床前有效性。据我们所知，这是第一次证明来自可食用植物的基于木脂素的膳食组分特异性地且显著地增强人NK细胞功能。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，因此该临床前研究具有相对较强的转化为临床的潜力，作为I期、II期和III期化学预防试验，在完成该研究后开始。 study.因此，我们的研究不仅具有创新性和重要性，而且具有高度的翻译性。