权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Rexinoid Synergy in Prostate Cancer Apoptosis

Rexinoid 在前列腺癌细胞凋亡中的协同作用

基本信息

批准号：
7347571
负责人：
MARCIA I. DAWSON
金额：
$ 51.04万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-04 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347571
关键词：
9-deoxy-delta-9-prostaglandin D2 AHPN Address Adverse effects Affect Agonist American Androgens Antineoplastic Agents Apoptosis Apoptotic BCL2 Gene Translocation Benign Bexarotene Binding Breast Cancer Cell C11 Chalcone Cancer Etiology Caspase Cell Line Cell Nucleus Cells Cessation of life Combined Modality Therapy Complement Complement component C1s Computer Analysis Cyclophosphamide Databases Dimerization Disease Docking Drug Combinations Drug usage Elements Estramustine Etodolac Etoposide Evaluation Facility Construction Funding Category Failure Family member Figs - dietary Goals Growth Heterodimerization Human In Vitro Incidence Invasive Libraries Ligand Binding Ligand Binding Domain Ligands Link Lung Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods Mitochondria Modality Modeling Molecular NR4A1 gene Nuclear Nuclear Export Nuclear Receptors Orphan Outcome Ovary Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Process Prostate Protein Overexpression Proteins RXR Regulatory Pathway Retinoic Acid Receptor Retinoids Role Score Screening procedure Signal Pathway Signal Transduction Stomach Structure-Activity Relationship Surface Synthesis Chemistry System Therapeutic Therapeutic Effect Therapeutic Index Tissues Toxic effect Transcriptional Activation Xenograft Model Xenograft procedure analog anticancer activity base cancer cell cancer type chemotherapeutic agent chemotherapy computer studies cross reactivity cytochrome c design dimer docetaxel improved in vivo interdisciplinary approach large cell Diffuse non-Hodgkin&apos s lymphoma member men mouse model neoplastic cell novel pharmacophore receptor response scaffold statistics virtual

项目摘要

DESCRIPTION (provided by applicant): Invasive prostate cancer continues to be a fatal disease, indicating that effective treatment modalities must be identified. Interestingly, we discovered that several retinoid X receptor (RXR) ligands (rexporters) potentiate the egress of the TR3/RXRalpha nuclear receptor heterodimer from the cancer cell nucleus to its mitochondria to facilitate apoptosis induced by several anti-prostate cancer drugs both in vitro and in vivo. Thus, both RXR and TR3 have extra nuclear functions. Export of TR3 requires RXR. The TR3/RXRalpha apoptosis pathway also involves the interaction of TR3 with mitochondrial surface-associated Bcl-2. On interacting with TR3, Bcl-2 undergoes a conformational change that reverses Bcl-2 function from a cell-protective protein to one supporting apoptosis involving the release of cytochrome c and the initiation of the caspase cascade. We hypothesize that because both TR3 and Bcl-2 are often overexpressed in prostate cancers, rexporters, which potentiate their interaction, in combination with apoptotic anti-prostate cancer drugs should have enhanced efficacy. We propose improving the therapeutic index (activity versus toxicity) of these rexporters by integrating synthesis with design guided by four major aims as follows: (1) Computational Studies. Identify more selective rexporters through novel computational studies involving rapid virtual structural database docking to RXRalpha complemented by pharmacophore construction. (2) Rexporter Synthesis. Enhance efficacy and TR3/RXR selectivity to reduce retinoid adverse effects by introducing new scaffolds and substituents based on Aims 1,3, and 4 results. (3) Role of TR3/RXRalpha in chemotherapy-induced prostate cancer apoptosis. Examine the role of RXR and its ligands in regulating TR3 activities through TR3/RXRalpha heterodimerization. Determine how rexporters enhance chemotherapeutic drug-induced prostate cancer apoptosis. (4) In vitro/In vivo Studies. Evaluate rexporter anticancer efficacy in vitro alone and in combination with an apoptotic anti-prostate cancer drug such as etoposide. The most efficacious rexporter-drug combinations in vitro will be evaluated in a prostate cancer xenograft model, and those active in vivo verified in the TRAMP mouse model. Synergistic/additive in vitro effects will be determined using isobologram methods. These studies will enhance our understanding of the molecular mechanisms underlying the anti-prostate cancer activity of chemotherapeutic drugs and the roles of TR3/RXRalpha and rexporter ligands in this process. We anticipate that our results will provide a more effective and less systemically toxic means of enhancing the efficacy of chemotherapeutic agents currently used to treat prostate cancer.

描述（由申请人提供）：侵袭性前列腺癌仍然是一种致命的疾病，表明必须确定有效的治疗方式。有趣的是，我们发现几种类维生素A X受体（RXR）配体（rexporter）增强TR 3/RXR α核受体异源二聚体从癌细胞核到其线粒体的出口，以促进几种抗前列腺癌药物在体外和体内诱导的细胞凋亡。因此，RXR和TR 3都具有额外的核功能。TR 3的导出需要RXR。TR 3/RXR α凋亡途径还涉及TR 3与线粒体表面相关Bcl-2的相互作用。在与TR 3相互作用时，Bcl-2发生构象变化，将Bcl-2功能从细胞保护蛋白逆转为支持细胞凋亡的蛋白，涉及细胞色素c的释放和半胱天冬酶级联的启动。我们假设，由于TR 3和Bcl-2在前列腺癌中经常过表达，因此加强其相互作用的rexporters与凋亡抗前列腺癌药物组合应该具有增强的功效。我们建议通过整合合成与设计来提高这些rexporter的治疗指数（活性与毒性），其主要目标如下：（1）计算研究。通过新的计算研究，包括快速虚拟结构数据库对接到RXR α，辅以药效团构建，确定更具选择性的rexporters。(2)Rexporter Synthesis.基于目标1、3和4的结果，通过引入新的支架和取代基，增强疗效和TR 3/RXR选择性，以减少类维生素A的不良反应。(3)TR 3/RXR α在化疗诱导的前列腺癌细胞凋亡中的作用检查RXR及其配体通过TR 3/RXR α异源二聚化调节TR 3活性的作用。确定受体如何增强化疗药物诱导的前列腺癌细胞凋亡。(4)体外/体内研究。评估rexporter单独和与凋亡抗前列腺癌药物如依托泊苷联合的体外抗癌功效。将在前列腺癌异种移植模型中评估体外最有效的受体-药物组合，并且在TRAMP小鼠模型中验证体内活性的那些。将使用等效线图方法确定体外协同/相加效应。这些研究将增强我们对化疗药物抗前列腺癌活性的分子机制以及TR 3/RXR α和rexporter配体在此过程中的作用的理解。我们预计，我们的研究结果将提供一个更有效和更少的全身毒性的手段，提高目前用于治疗前列腺癌的化疗药物的疗效。