Novel Inhibitors of Prostate Cancer Progression

前列腺癌进展的新型抑制剂

基本信息

批准号：
8197912
负责人：
AJIT K VERMA
金额：
$ 33.63万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197912
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Accounting Age Androgen Receptor Androgens Antioxidants Biological Assay Biological Availability Biological Markers Bioluminescence Cancer Etiology Cancer Patient Cell Survival Cells Cessation of life Chemopreventive Agent DNA Binding DU145 Development Diet Disease Distant Metastasis Drug Kinetics Femur Gelatinase B Gene Expression Genes Genetic Transcription Growth Health Hormones Human Image Implant India Interleukin-6 LNCaP Label Life Link Liver Luc Gene Luciferases Lung MAP2K1 gene Malignant neoplasm of prostate Mandible Mediating Medicinal Plants Medicine Modeling Molecular Target Mus NF-kappa B Naphthoquinones Neoplasm Metastasis Nuclear Nude Mice PC3 cell line PTGS2 gene Pathway interactions Pattern Phosphorylation Phosphotransferases Phytochemical Plant Roots Plants Plumbago Polymerase Chain Reaction Powder dose form Prevention Prostate Prostate Cancer therapy Protein Kinase Proto-Oncogene Proteins c-akt Publishing Receptor Activation Refractory Reporting Rodent SCID Mice Serine Signal Transduction Site Small Interfering RNA Somatotropin Specimen Staging Testing Time Tissues Transcription Factor AP-1 Tumor Volume Tumor Weights Variant Vascular Endothelial Growth Factors Vertebral column Work Xenograft Model Xenograft procedure androgen independent prostate cancer autocrine base bone cancer cell cyclooxygenase 2 cytokine deprivation dimer hormone refractory prostate cancer humerus implantation in vivo inhibitor/antagonist link protein lymph nodes male member men mouse model novel overexpression paracrine plumbagin prevent prostate cancer prevention protein expression receptor expression research study success survivin tibia transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The objective of this revised proposal is to investigate plumbagin, a medicinal plant-derived naphthoquinone, in the prevention of growth and metastasis of hormone refractory prostate cancer (PCa). Hormone refractory invasive PCa is the end stage and accounts for the majority of PCa patient deaths. The roots of Plumbago zeylanica L. have been used as medicine in India for more than 2500 years in treatment of various ailments. However, no study exits on the effects of plumbagin in the prevention and/or treatment of PCa progression. Our observations that prompted the exploration of plumbagin in the prevention of growth and metastasis of PCa include: A) Plumbagin inhibits invasion of androgen-independent (AI) PCa cells. B) Plumbagin administration delays ectopic growth of hormone refractory PCa cells as well as reduces both tumor weight and volume by 90%. C) In AI PCa cells, plumbagin inhibits the constitutive activation of Stat3, NF-kB, AP-1 and expression of protein kinase C5 (PKC5), the predictive biomarkers of PCa aggressiveness. We now propose to test two hypotheses: 1) Plumbagin prevents the growth and metastasis of hormone refractory PCa. 2) The key mechanism of AI PCa prevention involves the ability of plumbagin to inhibit: i) expression levels as well as activation of PKC5 and PKC5 downstream protein kinase cascades, ii) AR expression and activation and iii) Stat3 activation as well as Stat3-regulated gene expression linked to AI PCa cell survival and metastasis. Two specific aims are proposed to test the hypotheses. Specific Aim #1: to determine whether plumbagin prevents the progression and metastasis of hormone refractory PCa. To accomplish this, we propose to determine the effects of plumbagin on: 1A) the growth and metastasis of orthotopic xenografts of Luciferase- labeled AI PCa cells (C4-2B) in SCID mice. Luciferase-labeled cells will be implanted into the prostate and the metastatic dissemination pattern of PCa to various tissues including bone will be determined by bioluminescence imaging of live mice and by real time polymerase chain reaction (RT-PCR) assay for luciferase gene using isolated tissue from sacrificed mice. B) The progression and metastasis of AI PCa in a PCa mouse model (bigenic Nkx3.1-/-//Pten-/+ mice). The bigenic Nkx3.1-/-//Pten-/+ mice recapitulate stages of human prostate cancer progression. Specific Aim #2: To determine whether the mechanism of PCa prevention by plumbagin involves its ability to inhibit: i) PKC5, ii) androgen receptor (AR) and iii) Stat3 activation as well as Stat3-regulated gene expression. To accomplish this, we propose to: 2A) obtain first correlative evidence, by analysis of specimens collected in experiments proposed under Specific Aim 1, whether plumbagin-caused inhibition of PCa associates with expression levels of activated PKC5, PKC5 downstream protein kinase cascade, AR and Stat3 activation as well as Stat3-reulated gene expression. 2B) determine precisely the link of PKC5 and its associated signals using AD PCa cell line LNCaP and its AI derivative C4-2B. Plumbagin will be a novel agent to prevent and treat AI PCa. PUBLIC HEALTH RELEVANCE: Hormone refractory Prostate cancer (PCa) is the end stage and accounts for the majority of PCa patient deaths. There is urgent need for an agent which is effective and selective in the prevention and/or treatment of late stage hormone refractory PCa. Recently, we found that plumbagin, a medicinal plant-derived naphthoquinone, selectively inhibits PKC5 expression, growth and invasion of hormone refractory PCa cells. The proposed study will determine for the first time whether and how Plumbagin can prevent and treat hormone refractory PCa.

描述（由申请人提供）：这项修订的建议的目的是研究Plumbagin（一种药用植物来源的萘醌），以预防激素难治性前列腺癌（PCA）的生长和转移。激素难治性侵入性PCA是终点，占PCA患者死亡的大部分。 Plumbago Zeylanica L.的根源已在印度用作医学2500多年，用于治疗各种疾病。但是，尚无研究铅铅蛋白研究对PCA进展的预防和/或治疗的影响。我们的观察结果促使PCA预防铅铅蛋白探索的探索包括：a）plumbagin抑制了侵袭雄激素非依赖性（AI）PCA细胞的侵袭。 b）铅笔施用延迟了激素难治性PCA细胞的异位生长，并使肿瘤的重量和体积均减少90％。 c）在AI PCA细胞中，plumbagin抑制了STAT3，NF-KB，AP-1和蛋白激酶C5（PKC5）（PCA攻击性的预测性生物标志物）的本构激活。现在，我们建议检验两个假设：1）铅铅制可防止激素难治性PCA的生长和转移。 2）预防AI PCA的关键机制涉及铅铅制抑制的能力：i）表达水平以及PKC5和PKC5下游蛋白激酶级联反应的激活，ii）AR表达和激活以及III）STAT3激活以及STAT3调节的基因表达以及与AI PCA Cell Cell Cell Cell Survival和MetStasts链接的。提出了两个特定的目标来检验假设。具体目的＃1：确定铅铅蛋白是否可以防止激素难治性PCA的进展和转移。为此，我们建议确定plumbagin对：1a）荧光素酶 - 标记为AI PCA细胞（C4-2B）的原位异种移植物的生长和转移的作用。荧光素酶标记的细胞将植入前列腺，并通过生物发光成像和实时聚合酶链反应（RT-PCR）的生物发光成像来确定PCA向包括骨骼的各种组织的转移性传播模式，并使用来自牺牲小鼠的分离组织进行荧光素酶基因。 b）PCA小鼠模型中AI PCA的进展和转移（bigenic nkx3.1 - / - / - / - //pten-/+小鼠）。 BiLenic NKX3.1 - / - // PTEN-/+小鼠概括了人类前列腺癌进展的阶段。具体目的＃2：确定PCA预防PCA的机制是否涉及其抑制能力：i）PKC5，ii）雄激素受体（AR）和III）STAT3激活以及STAT3调节的基因表达。为此，我们提出：2a）获得第一个相关证据，通过对在特定目标1提出的实验中收集的标本中收集的标本1，是否对PCA引起的PCA抑制是否与活化PKC5的表达水平，PKC5 PKC5抑制，PKC5下游蛋白激酶级别，AR AR AR和Stat3活化的Gene 3-含量均得到了统计3-含量。 2b）精确地确定了使用AD PCA细胞系LNCAP及其AI衍生物C4-2B的PKC5及其相关信号的链接。 Plumbagin将是预防和治疗AI PCA的新型药物。公共卫生相关性：激素难治性前列腺癌（PCA）是终点，占PCA患者的大部分。迫切需要一种在预防和/或治疗后期激素难治性PCA方面具有有效和选择性的代理。最近，我们发现Plumbagin是一种药用植物衍生的萘酮，有选择地抑制PKC5表达，生长和侵袭激素难治性PCA细胞。拟议的研究将首次确定plumbagin是否以及如何预防和治疗激素难治性PCA。