Rexinoid Synergy in Prostate Cancer Apoptosis

Rexinoid 在前列腺癌细胞凋亡中的协同作用

• 批准号: 7014084
• 负责人: MARCIA I. DAWSON
• 金额: $ 49.12万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 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/7014084
• 关键词: BCL2 gene /protein; antineoplastics; apoptosis; combinatorial chemistry; confocal scanning microscopy; drug design /synthesis /production; drug discovery /isolation; drug interactions; drug screening /evaluation; enzyme linked immunosorbent assay; green fluorescent proteins; immunoprecipitation; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; nuclear receptors; nuclear transfer; pharmacokinetics; prostate neoplasms; protein protein interaction; protein structure function; receptor binding; receptor expression; retinoid binding proteins; small interfering RNA; terminal nick end labeling

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，我们发现几种视黄酸X受体（RXR）配体（再输出蛋白）可增强TR3/RXRα核受体异二聚体从癌细胞核到线粒体的出口，以促进几种抗前列腺癌药物在体外和体外诱导的细胞凋亡。体内。因此，RXR和TR3都具有额外的核功能。 TR3的导出需要RXR。 TR3/RXRα 凋亡途径还涉及 TR3 与线粒体表面相关 Bcl-2 的相互作用。在与 TR3 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 caspase 级联的启动。我们推测，由于 TR3 和 Bcl-2 在前列腺癌中经常过度表达，因此增强它们相互作用的再输出蛋白与凋亡抗前列腺癌药物联合使用应该会增强疗效。我们建议通过将合成与设计相结合来提高这些再输出蛋白的治疗指数（活性与毒性），以下四个主要目标为指导：（1）计算研究。通过新颖的计算研究，包括快速虚拟结构数据库对接 RXRalpha 并辅以药效基团构建，识别更具选择性的再输出蛋白。 (2)Reporter合成。根据目标 1,3 和 4 结果引入新的支架和取代基，增强功效和 TR3/RXR 选择性，以减少类维生素A的副作用。 (3)TR3/RXRα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 TR3/RXRα 异二聚化调节 TR3 活性的作用。确定再输出蛋白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。单独评估再输出蛋白以及与依托泊苷等凋亡抗前列腺癌药物联合使用的体外抗癌功效。将在前列腺癌异种移植模型中评估体外最有效的再输出药物组合，并在 TRAMP 小鼠模型中验证体内有效的组合。体外协同/累加效应将使用等效线图方法来确定。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TR3/RXRα和reporter配体在此过程中的作用的理解。我们预计我们的结果将提供一种更有效且系统毒性更小的方法来增强目前用于治疗前列腺癌的化疗药物的功效。