Prostate Cancer Chemoprevention using a Natural Agent

使用天然药物化学预防前列腺癌

• 批准号: 8445062
• 负责人: Shailesh Singh
• 金额: $ 18.47万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445062
• 关键词: Adopted; Andrographis; Animals; Antibodies; Applications Grants; B-Lymphocytes; Biological Assay; C57BL/6 Mouse; Cancer Patient; Cell Count; Cell Proliferation; Cell Survival; Cell physiology; Cell-Mediated Cytolysis; Cells; Chemoprevention; Chemopreventive Agent; Color; Cytolysis; Cytoplasmic Granules; Data; Dendritic Cells; Development; Disease; Effectiveness; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Growth; Host Defense; Image; Immune; Immune response; Immune system; Immunohistochemistry; Immunologic Surveillance; In Vitro; Incidence; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Mature T-Lymphocyte; Modeling; Molecular; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Neoplastic Cell Transformation; Oral Administration; PTEN gene; Patients; Phenotype; Prevention; Production; Prostatic Neoplasms; Recruitment Activity; Role; Serine Protease; Serum; Site; System; T cell response; T-Lymphocyte; Testing; Toxic effect; Translating; Tumor Immunity; Tumor-Infiltrating Lymphocytes; andrographolide; base; bioluminescence imaging; cancer cell; cancer chemoprevention; clinical application; clinically relevant; cytokine; cytotoxic; granulysin; in vivo; innovation; insight; killings; lymphoblast; male; monocyte; mouse model; neoplastic cell; novel; perforin; prostate cancer cell; prostate cancer model; prostate cancer prevention; public health relevance; research study; restoration; treatment strategy; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The long latency of prostate cancer (PCa) provides a window of opportunity for chemoprevention strategies. Most such strategies are focused on controling and/or reversing the mechanisms involved in neoplastic transformation and cancer progression. It is well accepted that, during development and progression, tumor cells evade the patient's defense system. In this regard, natural killer (NK) cells are cellular effectors of the innate immune system and are required for activation of the host defense system and for destruction of tumor cells. In PCa patients, however, the function of NK cells and their numbers are often compromised and/or depleted. Therefore, enhancing the function of NK cells by immunomodulatory compounds is a promising approach for PCa prevention. Recently, we demonstrated the immunomodulatory effects of andrographolide (AG), a natural compound isolated from Andrographis paniculata (AP), on NK cells and have established its antitumor effects in mice bearing PCa PTEN syngeneic tumors. Our preliminary results provide a rationale to investigate the function of AG in potentiating NK cells, which can act to eliminate PCa cells. Based on these encouraging preliminary data, we hypothesize that AG inhibits PCa growth by potentiating the anti-tumor activity of NK cells, thus offering an innovative, immune-based chemopreventive strategy for PCa. To test this hypothesis, we propose two specific aims. The first aim will use mouse models to determine the potential of AG in boosting NK cell activity against PCa. This will be achieved by establishing an interrelationship between the in vivo effects of AG through NK cel mobilization and cytotoxic activities and the effectiveness of AG in adaptive T cell responses through modulation of cytokine production by NK cells. In the second aim, we will establish the effects of AG on development, proliferation/survival, and cytotoxic function of NK cells. These studies, which will determine the effectiveness of AG in PCa chemoprevention achieved through boosting NK cell function, make the proposal clinically relevant and highly translational.

描述（由申请人提供）：前列腺癌（PCa）的长潜伏期为化学预防策略提供了机会之窗。大多数此类策略侧重于控制和/或逆转肿瘤转化和癌症进展所涉及的机制。人们普遍认为，在发育和进展过程中，肿瘤细胞会逃避患者的防御系统。在这方面，自然杀伤（NK）细胞是先天免疫系统的细胞效应器，是激活宿主防御系统和破坏肿瘤细胞所必需的。然而，在前列腺癌患者中，NK 细胞的功能及其数量常常受到损害和/或耗尽。因此，通过免疫调节化合物增强 NK 细胞的功能是预防 PCa 的一种有前途的方法。最近，我们证明了穿心莲内酯 (AG)（一种从穿心莲 (AP) 中分离出的天然化合物）对 NK 细胞的免疫调节作用，并在携带 PCa PTEN 同基因肿瘤的小鼠中确定了其抗肿瘤作用。我们的初步结果为研究 AG 在增强 NK 细胞中的功能提供了理论基础，NK 细胞可以起到消除 PCa 细胞的作用。基于这些令人鼓舞的初步数据，我们假设 AG 通过增强 NK 细胞的抗肿瘤活性来抑制 PCa 生长，从而为 PCa 提供一种创新的、基于免疫的化学预防策略。为了检验这一假设，我们提出了两个具体目标。第一个目标是使用小鼠模型来确定 AG 在增强 NK 细胞对抗 PCa 活性方面​​的潜力。这将通过建立 AG 通过 NK 细胞动员和细胞毒活性产生的体内效应与 AG 通过调节 NK 细胞产生的细胞因子在适应性 T 细胞反应中的有效性之间的相互关系来实现。在第二个目标中，我们将确定 AG 对 NK 细胞的发育、增殖/存活和细胞毒功能的影响。这些研究将确定 AG 在通过增强 NK 细胞功能实现 PCa 化学预防中的有效性，使该提案具有临床相关性和高度转化性。