Novel Targets of Indoles in Prostate Cancer

吲哚治疗前列腺癌的新靶点

基本信息

批准号：
8403538
负责人：
FAZLUL H. SARKAR
金额：
$ 27.75万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403538
关键词：
Ablation Age-Years Androgen Receptor Androgens Animal Model Animals Apoptosis Apoptotic Biological Bone neoplasms CWR22Rv1 Cancer Cell Growth Cancer Etiology Cancer Patient Cell Death Cell Death Inhibition Cell Line Cell Proliferation Cell Survival Cells Cessation of life Characteristics Clinical Research Clinical Trials Communities Consumption DU145 Data Dependence Development Diagnosis Dietary Factors Disease Dose Down-Regulation Epidemiologic Studies Epithelial Epithelial Cells Exclusion Funding Gene Targeting Gene Transfer General Population Growth Herb Hormones Human Human Development In Vitro Indole-3-Carbinol Indoles Induction of Apoptosis Inhibition of Cell Proliferation Intervention Investigation Knowledge LNCaP MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Micronutrients Minority Molecular Mutate Names Neoplasm Metastasis Nuclear Oncogenic Operative Surgical Procedures Oral Oral Administration PC3 cell line Pathway interactions Patients Phase Phase I Clinical Trials Phosphorylation Phytochemical Prevention Prevention strategy Prevention therapy Preventive Process Prostate Prostate carcinoma Prostatic Neoplasms Public Health Publications Receptor Cell Receptor Signaling Refractory Regulation Reporting Research Residual Tumors Resistance Role Serum Signal Pathway Signal Transduction Specimen Staging Testing Therapeutic Tissue Harvesting Tissues Transcriptional Regulation Tumor Tissue Xenograft Model androgen independent prostate cancer angiogenesis antitumor agent base bone cancer cell cancer prevention cancer therapy capsule cell growth chemotherapy design dietary supplements diindolylmethane docetaxel fruits and vegetables hormone refractory prostate cancer human disease in vitro testing in vivo innovation interest killings male men mutant neoplastic cell novel novel strategies prostate cancer cell protective effect public health relevance receptor function research study response steroid hormone therapy development treatment strategy tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The majority of prostate cancer (PCa) patients treated with hormone ablation therapy develop hormone refractory prostate cancer (HRPC), and leads to predominant bone metastatic disease that still contains Akt- activated functional androgen receptor (AR), and for which there is no curative therapy. In HRPC (also known as castrate resistant tumors) and bone metastatic disease, AR functions promiscuously, at least, due to the activation of Akt signaling. Therefore it is important to understand how Akt activates AR, and most importantly develop a non-toxic strategy by which AR in PCa could be totally inactivated; thereby growth response via AR signaling could be totally destroyed. Previous studies have shown that consumption of fruits and vegetables provides indole compounds [indole-3-carbinol (I3C) and its in vivo product 3-3'-diindolylmethane (DIM)] that are believed to be protective against the development of human PCa. Our studies during the preceding funding period showed that DIM and a well-standardized formulated DIM obtained from BioResponse, named BR-DIM (hereafter referred as B-DIM), down-regulated Akt, NF-:B, AR, 2-catenin and PSA, and induced apoptotic cell death of PCa cell lines but not normal prostate epithelial cells. Moreover, we have shown that DIM could inhibit invasion and angiogenesis. Based on our preliminary results and the existing knowledge on Akt/Wnt/AR signaling, we hypothesize that 2-catenin is a critical molecule for the signal transduction between Akt, Wnt, and AR signaling network and that the use of B-DIM will serve as a novel approach by which the progression, invasion, and metastasis of PCa could be inhibited through the regulation of 2-catenin mediated Akt/Wnt/AR signaling. We further hypothesize that B-DIM will elicit anti-tumor activity in animal model and that B-DIM could be targeted to human prostate gland in PCa patient. To test our hypotheses, we designed four specific aims where androgen sensitive (LNCaP, mutant AR+) and androgen insensitive (LNCaP derived C4- 2B and CWR22Rv1, mutant AR+) cells will be used to answer the following questions: (a) how Akt regulates Wnt signaling via 2-catenin pathway, (b) how 2-catenin regulates AR signaling, (c) whether B-DIM has any direct effect on Wnt signaling in regulating cell proliferation and apoptosis, (d) whether B-DIM has any direct effect on 2-catenin mediated signal transduction and AR trans-activation, (e) whether B-DIM mediated inhibition of PCa cell growth and induction of apoptosis in vitro and in vivo could in part be due to the regulation of 2-catenin mediated signal transduction, and finally (f) does exposure of PCa patients to B-DIM will show B-DIM accumulation in the prostate tumor, which may result in the down-regulation of AR and NF- :B, and nuclear exclusion of 2-catenin. Understanding of the molecular and cellular mechanism by which Akt activates AR and how B-DIM inactivates AR signaling, will have a significant impact on designing non-toxic strategies for the prevention of tumor progression and/or treatment of PCa patients. Thus our proposal is innovative and highly relevant to public health in general and for PCa patients in particular.

描述（由申请人提供）：用激素消融疗法治疗的大多数前列腺癌（PCA）患者会产生激素难治性前列腺癌（HRPC），并导致主要的骨转移性疾病，但仍含有AKT活化的功能性雄激素受体（AR），并且没有治疗疗法。在HRPC（也称为castrate耐药性肿瘤）和骨转移性疾病中，AR至少由于AKT信号的激活而起作用。因此，重要的是要了解AKT如何激活AR，最重要的是开发一种无毒策略，通过该策略可以完全灭活PCA中的AR。因此，通过AR信号传导的增长响应可能会被完全破坏。先前的研究表明，食用水果和蔬菜提供吲哚化合物[吲哚-3-甲醇（I3C）及其体内产物3-3'-二烷基甲烷（DIM）]，据信可以保护人类PCA的发展。我们在上一个资金期间的研究表明，从生物响应中获得的昏暗和标准化的配方型昏暗（以下称为B-DIM），下调的Akt，NF-：B，AR，AR，2-catenin和psa，以及诱导的PCA细胞线的凋亡细胞死亡，但不是正常的前列腺素细胞。此外，我们已经表明DIM可以抑制侵袭和血管生成。 Based on our preliminary results and the existing knowledge on Akt/Wnt/AR signaling, we hypothesize that 2-catenin is a critical molecule for the signal transduction between Akt, Wnt, and AR signaling network and that the use of B-DIM will serve as a novel approach by which the progression, invasion, and metastasis of PCa could be inhibited through the regulation of 2-catenin mediated Akt/Wnt/AR信号。我们进一步假设B-DIM将在动物模型中引起抗肿瘤活性，并且B-DIM可以针对PCA患者的人类前列腺。为了检验我们的假设，我们设计了四个特定目的，其中雄激素敏感（LNCAP，突变体AR+）和雄激素不敏感（LNCAP得出的C4-2B和CWR22RV1得出的LNCAP衍生得出，突变体AR+）将使用以下问题来回答以下问题：（a）如何通过2-Catenin pation（a）调节WNTS信号（a）。 B-DIM has any direct effect on Wnt signaling in regulating cell proliferation and apoptosis, (d) whether B-DIM has any direct effect on 2-catenin mediated signal transduction and AR trans-activation, (e) whether B-DIM mediated inhibition of PCa cell growth and induction of apoptosis in vitro and in vivo could in part be due to the regulation of 2-catenin mediated signal transduction, and finally (f) does PCA患者暴露于B-DIM将显示B-DIM在前列腺肿瘤中的积累，这可能导致AR和NF-：B的下调以及2-catenin的核排斥。了解AKT激活AR以及B-DIM如何使AR信号传导的分子和细胞机制的理解将对设计无毒策略产生重大影响，以预防PCA患者的肿瘤进展和/或治疗。因此，我们的建议具有创新性，并且与一般公共卫生，尤其是PCA患者高度相关。