Novel Targets of Indoles in Prostate Cancer

吲哚治疗前列腺癌的新靶点

• 批准号: 8011073
• 负责人: FAZLUL H. SARKAR
• 金额: $ 29.52万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8011073
• 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; 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; protective effect; public health relevance; receptor function; research study; response; steroid hormone; therapy development; treatment strategy; tumor; tumor growth; tumor progression

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. PUBLIC HEALTH RELEVANCE: This competing renewal application is focused on elucidating the mechanism by which Akt/Wnt activates AR, and assessing how a chemo-preventive agent (B-DIM) could inactivate AR signaling resulting in the inhibition of prostate cancer (PCa) cell growth, invasion and angiogenesis, and causing anti-tumor activity in an animal model. Moreover, based on our phase I clinical trial, we will also conduct a phase II clinical study for assessing whether B-DIM could reach prostate gland and elicit biological effects in PCa patients receiving oral B-DIM. The results of our study will help to design mechanism-based clinical trials for assessing the role of B-DIM in the prevention and/or treatment of PCa.

描述（由申请人提供）： 大多数接受激素消融治疗的前列腺癌 (PCa) 患者会发展为激素难治性前列腺癌 (HRPC)，并导致主要的骨转移性疾病，该疾病仍含有 Akt 激活的功能性雄激素受体 (AR)，且尚无治疗方法治疗。在 HRPC（也称为去势抵抗性肿瘤）和骨转移性疾病中，AR 的功能混杂，至少是由于 Akt 信号传导的激活。因此，了解 Akt 如何激活 AR 非常重要，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 信号传导的生长反应可能会被完全破坏。先前的研究表明，食用水果和蔬菜可提供吲哚化合物[吲哚-3-甲醇 (I3C) 及其体内产物 3-3'-二吲哚基甲烷 (DIM)]，据信可预防人类 PCa 的发展。我们在之前的资助期间的研究表明，DIM 和从 BioResponse 获得的标准化配方 DIM，名为 BR-DIM（以下简称 B-DIM），下调了 Akt、NF-:B、AR、2-catenin 和PSA，并诱导 PCa 细胞系凋亡细胞死亡，但不诱导正常前列腺上皮细胞。此外，我们已经证明 DIM 可以抑制侵袭和血管生成。根据我们的初步结果和对 Akt/Wnt/AR 信号传导的现有知识，我们假设 2-catenin 是 Akt、Wnt 和 AR 信号网络之间信号转导的关键分子，并且 B-DIM 的使用将有助于作为一种新方法，可以通过调节 2-catenin 介导的 Akt/Wnt/AR 信号传导来抑制 PCa 的进展、侵袭和转移。我们进一步假设 B-DIM 将在动物模型中引发抗肿瘤活性，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，我们设计了四个具体目标，其中雄激素敏感（LNCaP，突变 AR+）和雄激素不敏感（LNCaP 衍生的 C4-2B 和 CWR22Rv1，突变 AR+）细胞将用于回答以下问题：（a）Akt 如何调节通过 2-catenin 通路的 Wnt 信号传导，(b) 2-catenin 如何调节 AR 信号传导，(c) B-DIM 是否对 Wnt 信号传导有任何直接影响(d) B-DIM 是否对 2-catenin 介导的信号转导和 AR 反式激活有直接影响，(e) B-DIM 是否介导体外抑制 PCa 细胞生长和诱导细胞凋亡在体内，部分原因可能是由于 2-连环蛋白介导的信号转导的调节，最后 (f) PCa 患者暴露于 B-DIM 是否会显示 B-DIM 在前列腺肿瘤中积聚，这可能导致AR 和 NF-:B 下调，以及 2-连环蛋白的核排除。了解 Akt 激活 AR 的分子和细胞机制以及 B-DIM 如何灭活 AR 信号传导，将对设计预防肿瘤进展和/或治疗 PCa 患者的无毒策略产生重大影响。因此，我们的建议具有创新性，并且与一般公众健康，特别是前列腺癌患者高度相关。 公共卫生相关性： 这项竞争性更新应用的重点是阐明 Akt/Wnt 激活 AR 的机制，并评估化学预防剂 (B-DIM) 如何灭活 AR 信号传导，从而抑制前列腺癌 (PCa) 细胞的生长、侵袭和生长。血管生成，并在动物模型中引起抗肿瘤活性。此外，基于我们的I期临床试验，我们还将进行II期临床研究，以评估B-DIM是否可以到达前列腺并在接受口服B-DIM的前列腺癌患者中产生生物效应。我们的研究结果将有助于设计基于机制的临床试验，以评估 B-DIM 在预防和/或治疗 PCa 中的作用。