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的疾病，这表明必须确定有效的治疗方式。有趣的是，我们发现几种维甲酸X受体(RXR)配体(Rexporter)增强了TR3/RXRpha核受体异二聚体从癌细胞核到其线粒体的外流，从而促进了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TR3都具有额外的核功能。出口TR3需要RXR。TR3/RXRpha凋亡通路还涉及TR3与线粒体表面相关的Bcl2的相互作用。与TR3相互作用后，Bcl2发生构象变化，将Bcl2的功能从细胞保护性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表达，加强它们之间相互作用的重组子，与抗前列腺癌药物联合使用应该有更好的疗效。我们建议在以下四个主要目标的指导下，通过将合成与设计相结合来提高这些重组体的治疗指数(活性与毒性)：(1)计算研究。通过新的计算研究确定更多的选择性重组子，包括快速虚拟结构数据库对接到RXRpha，并辅之以药效团的构建。(2)Rexporter合成。根据目标1、3和4的结果，通过引入新的支架和取代基来提高疗效和TR3/RXR的选择性，以减少维甲酸的不良反应。(3)TR3/RXRpha在化疗诱导前列腺癌细胞凋亡中的作用。研究RXR及其配体通过TR3/RXRα异源二聚作用调节TR3活性的作用。确定rex转运体如何促进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单独和联合使用抗前列腺癌药物如依托泊苷的体外抗癌效果。体外最有效的Rexporter-药物组合将在前列腺癌异种移植模型中进行评估，而那些在体内活跃的药物组合将在TRAMP小鼠模型中得到验证。体外协同/相加效应将用等同线图法确定。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/RXRpha和Rexporter配体在这一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、系统毒性更小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.