Rexinoid Synergy in Prostate Cancer Apoptosis

描述（由申请人提供）：浸润性前列腺癌仍然是一种致命疾病，表明必须确定有效的治疗方式。有趣的是，我们在体外和体内均发现，几种类视黄醇X受体（RXR）配体（报告者）可增强TR3/RXR α核受体异二聚体从癌细胞细胞核向线粒体的出口，从而促进几种抗前列腺癌药物诱导的细胞凋亡。因此，RXR和TR3都具有额外的核功能。TR3出口需要RXR。TR3/ rxrα凋亡途径也涉及TR3与线粒体表面相关的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的功能从细胞保护蛋白转变为支持凋亡的蛋白，包括细胞色素c的释放和caspase级联反应的启动。我们假设，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报告蛋白与凋亡性抗前列腺癌药物联合使用应该会增强疗效。我们建议在以下四个主要目标的指导下，通过综合与设计来提高这些报告者的治疗指数（活性与毒性）：(1)计算研究。通过新颖的计算研究，包括与RXRalpha的快速虚拟结构数据库对接，并辅以药效团构建，确定更多的选择性记者。(2)报告综合。基于Aims 1,3,4的结果，通过引入新的支架和取代基来增强疗效和TR3/RXR选择性，以减少类维生素a的不良反应。(3) TR3/ rxrα在化疗诱导的前列腺癌细胞凋亡中的作用。研究RXR及其配体通过TR3/ rxrα异源二聚化调节TR3活性的作用。确定报告者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。评估报告者在体外单独和与凋亡抗前列腺癌药物（如依托泊苷）联合的抗癌效果。体外最有效的报告因子-药物组合将在前列腺癌异种移植模型中进行评估，并在TRAMP小鼠模型中验证体内有效的报告因子-药物组合。协同/加性体外效应将使用等线图方法确定。这些研究将加深我们对化疗药物抗前列腺癌活性的分子机制以及TR3/ rxrα和报告配体在这一过程中的作用的理解。我们期望我们的结果将提供一种更有效和更少系统毒性的方法来提高目前用于治疗前列腺癌的化疗药物的疗效。

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.