Nucleolin--A Novel Target for Cancer Drug Discovery

描述：(申请人提供) 本应用程序的目标是验证核仁素作为一种新的靶点 癌症的治疗干预。核仁素的鉴定 非反义富含G蛋白的发现引发了分子靶点 具有显著生长抑制作用的寡核苷酸(GROS) 许多实体瘤和白血病细胞系。两者之间存在广泛的相关性 GROS的抗增殖活性与其结合能力之间的关系 核仁蛋白。核仁蛋白是一种多功能核仁蛋白 与细胞生长密切相关，也存在于细胞表面。 已知在恶性细胞中核仁素水平比 正常细胞，初步数据表明，靶向策略 核仁素将具有肿瘤选择性。尽管格罗夫自己也有 相当大的治疗潜力，寡核苷酸的输送仍然是一个 临床应用的主要障碍，以及替代品的开发 核仁素抑制剂是可取的。调查人员已经开发出 筛选可用于鉴定小分子或多肽的分析方法 化合物文库中的核仁素抑制剂。核仁素也是可以访问的 合理的药物设计方法，由于结构的可获得性 关于相似蛋白质的信息。在如此广泛的发展研究之前 首先，有必要进一步验证核仁素是一种新的靶标 用于药物研发。因此，这项建议的总体目标是 证明核仁素表达或功能的调节导致肿瘤- 选择性抑制细胞生长。为此，拥有 核仁的可诱导下调或过度表达将被开发和 特色化的。反义寡核苷酸也将被用于靶向 抑制核仁素的表达。为了评估肿瘤的选择性， 细胞增殖率、核仁素水平与细胞增殖的关系 对GROS的敏感性，将进一步探讨。此外，该机制通过 将通过确定哪种核素介导生长抑制来检验 使用分子技术和蛋白质组学，GRO诱导核仁的变化。 预计蛋白质组学实验将检测蛋白质的变化 在GRO处理细胞中的表达也将阐明GRO的新机制 并可能识别参与其中的其他蛋白质靶点 细胞生长受阻。

DESCRIPTION: (provided by applicant) The goal of this application is to validate nucleolin as a novel target for therapeutic intervention in cancer. The identification of nucleolin as a molecular target has resulted from the discovery of non-antisense G-rich oligonucleotides (GROs) that have profound growth inhibitory effects against many solid tumor and leukemia cell lines. There is an extensive correlation between the antiproliferative activity of the GROs and their ability to bind to nucleolin protein. Nucleolin is a multifunctional nucleolar protein critically involved in cell growth, and also present on the cell surface. Levels of nucleolin are known to be elevated in malignant cells compared to normal cells, and preliminary data indicate that strategies to target nucleolin will be tumor-selective. Although the GROs themselves have considerable therapeutic potential, delivery of oligonucleotides remains a major obstacle to their clinical use, and the development of alternative nucleolin inhibitors is desirable. The investigators have already developed screening assays that can be used to identify small molecule or peptide inhibitors of nucleolin from compound libraries. Nucleolin is also accessible to rational drug design methods, due to the availability of structural information on similar proteins. Before such extensive development studies can begin, it will be necessary to further validate nucleolin as a novel target for drug discovery. The overall aim of this proposal is therefore to demonstrate that modulation of nucleolin expression or function causes tumor- selective inhibition of cell growth. To this end, cell lines that have inducible down-regulation or overexpression of nucleolin will be developed and characterized. Antisense oligonucleotides will also be used to target inhibition of nucleolin expression. To evaluate tumor-selectivity, the relationship between cell proliferation rate, levels of nucleolin, and sensitivity to GROs, will be further explored. In addition, the mechanism by which nucleolin mediates growth inhibition will be examined by determining GRO-induced changes in nucleolin, using molecular techniques and proteomics. It is anticipated that proteomics experiments to detect changes in protein expression in GRO-treated cells will also elucidate the novel mechanism of GRO effects and will potentially identify other protein targets that participate in cell growth arrest.