Prostate Cancer Chemoprevention using a Natural Agent

使用天然药物化学预防前列腺癌

基本信息

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
项目类别：
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

项目摘要

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）的长期潜伏期为化学预防策略提供了机会之窗。大多数此类策略都集中在控制和/或逆转肿瘤转化和癌症进展的机制上。众所周知，在发育和进展过程中，肿瘤细胞逃避了患者的防御系统。在这方面，天然杀伤（NK）细胞是先天免疫系统的细胞效应子，是激活宿主防御系统和破坏肿瘤细胞所必需的。但是，在PCA患者中，NK细胞的功能及其数量通常会损害和/或耗尽。因此，通过免疫调节化合物增强NK细胞的功能是PCA预防的有前途的方法。最近，我们证明了Andrographolide（Ag）的免疫调节作用，Andrographolide（Ag）是一种自然化合物（AP）对NK细胞的自然化合物（AP），并在具有PCA PTEN同步肿瘤的小鼠中建立了抗肿瘤作用。我们的初步结果提供了研究Ag在增强NK细胞中功能的基本原理，该功能可以消除PCA细胞。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的生长，从而为PCA提供创新的，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。第一个目的将使用小鼠模型来确定AG在对PCA中增强NK细胞活性的潜力。这将通过建立通过NK CEL动员和细胞毒性活性的体内影响与Ag通过调节NK细胞的细胞因子产生的自适应T细胞反应的有效性来实现这一目标。在第二个目标中，我们将建立AG对NK细胞的发育，增殖/生存和细胞毒性功能的影响。这些研究将决定AG通过促进NK细胞功能实现的PCA化学预防的有效性，这使该提案在临床上相关且高度转化。