Capitalizing on NSAID enantiomer selectivity for cancer prevention and therapy(PQ

利用 NSAID 对映体选择性进行癌症预防和治疗 (PQ

• 批准号: 8519391
• 负责人: LAURIE G HUDSON
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519391
• 关键词: Acetic Acids; Actins; Address; Adhesions; Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Binding; Biochemical; Cell Adhesion; Cellular Assay; Chemicals; Chemistry; Chemoprevention; Chemopreventive Agent; Clinical Trials; Coupled; Coupling; Data; Development; Drug usage; Enzyme Activation; Enzymes; Epidemiology; FDA approved; Family; Foundations; GTP Binding; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Incidence; Investigation; Kansas; Ketorolac; Knowledge; Lead; Legal patent; Malignant Neoplasms; Marketing; Molecular; Molecular Bank; Monomeric GTP-Binding Proteins; Naphthalene; Naproxen; Neoplasm Metastasis; New Mexico; Ovarian; Pathway interactions; Pharmaceutical Preparations; Pharmacology and Toxicology; Prevention; Production; Prostaglandin-Endoperoxide Synthase; Protein Isoprenylation; Proteins; Publishing; Resources; Role; Stratification; Structure; Testing; Thalidomide; Therapeutic; Toxic effect; United States National Institutes of Health; Universities; Work; Xenograft Model; base; bench to bedside; cancer prevention; cancer therapy; cheminformatics; clinical application; enantiomer; implantation; inhibitor/antagonist; innovation; insight; intraperitoneal; meetings; migration; mortality; neoplastic cell; non-drug; novel; ovarian neoplasm; population based; prevent; response; rho; scaffold; stem; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Provocative question (PQ) 5 challenges us to determine the mechanism whereby 'drugs commonly used for other indications, such as anti-inflammatory drugs (NSAIDs), can protect against cancer incidence and mortality'. Strong preliminary data lead us to propose that for certain chemical entities the chemopreventive and/or anti-tumor activity is attributable to interaction of the R-enantiomer of select NSAIDs with novel cancer- relevant targets. There are many examples of stereoselective differences in drug activity. The R-forms of non- steroidal anti-inflammatory drugs (NSAIDs) are essentially inactive against cyclooxygenases and there is mounting evidence that R-enantiomers are distinct chemical entities with independent pharmacologic activities. We find that the R-enantiomers of naproxen and ketorolac inhibit the small GTPases Rac1 and Cdc42. More than 20 other NSAIDs were inactive against these proteins, suggesting novel target selectivity by R-naproxen and R-ketorolac. Rac1 and Cdc42 regulate cytoskeletal dynamics in addition to other functions, and have been recognized as attractive cancer therapeutic targets although no specific inhibitors are currently in clinical trials. In keeping with the known functions of Rac1/Cdc42 in regulating actin-based functions, we find enantiomer- selective inhibition of ovarian tumor cell migration and adhesion. Furthermore, R-naproxen, but not S-naproxen or the structurally-related 6-methoxy naphthalene acetic acid (6-MNA), reduced implantation of ovarian tumors by ~75% in an intraperitoneal xenograft model. The objective of this application is to define the mechanism of action for the observed biologic activities of R-naproxen and R-ketorolac. This will provide the foundations for re-consideration of potential anti-tumor activities of other NSAID R-enantiomers based on interaction with novel targets. We hypothesize that R-ketorolac and R-naproxen inhibit Rac1 and/or Cdc42 and associated cellular responses through a novel mechanism based on drug binding to the GDP-bound (inactive) form of the enzymes. We will test this hypothesis by using biochemical and cellular approaches coupled with structure- activity analyses, we will test whether there is R-enantiomer-selective interaction with the GDP-bound forms of the GTPases as predicted by cheminformatics, leading to blockade of GTP binding, enzyme activation and downstream cellular responses. The work is significant because the novel pharmacologic and tumor-relevant functional activities of NSAID R-enantiomers have not been previously described and successful completion of the project will offer new mechanistic insights into the anti-cancer benefit of NSAIDS. The studies will also yield additional and critical information on the benefits of targeting Rac1 and Cdc42 in ovarian and other cancers.

描述（由申请人提供）：挑衅性问题（PQ）5要求我们确定“常用于其他适应症的药物，例如抗炎药（NSAID），可以预防癌症发病率和死亡率”的机制。强有力的初步数据使我们提出，对于某些化学实体，化学预防和/或抗肿瘤活性可归因于选定 NSAID 的 R 对映异构体与 新的癌症相关靶点。药物活性的立体选择性差异的例子有很多。非甾体抗炎药 (NSAID) 的 R 型基本上对环氧合酶无活性，并且越来越多的证据表明 R 对映异构体是具有独立药理活性的独特化学实体。我们发现萘普生和酮咯酸的 R 对映体抑制小 GTP 酶 Rac1 和 Cdc42。超过 20 种其他 NSAID 对这些蛋白质没有活性，表明 R-萘普生和 R-酮咯酸具有新的靶点选择性。 Rac1 和 Cdc42 除其他功能外还调节细胞骨架动力学，并已被认为是有吸引力的癌症治疗靶点，尽管目前尚无特定抑制剂正在进行临床试验。与 Rac1/Cdc42 调节基于肌动蛋白的功能的已知功能一致，我们发现对映体选择性抑制卵巢肿瘤细胞迁移和粘附。此外，在腹膜内异种移植模型中，R-萘普生（而非 S-萘普生或结构相关的 6-甲氧基萘乙酸 (6-MNA)）可将卵巢肿瘤的植入减少约 75%。本申请的目的是确定观察到的 R-萘普生和 R-酮咯酸生物活性的作用机制。这将为重新考虑其他 NSAID R-对映异构体基于与新靶点相互作用的潜在抗肿瘤活性奠定基础。我们假设 R-酮咯酸和 R-萘普生通过一种基于药物与 GDP 结合（无活性）形式的酶结合的新机制来抑制 Rac1 和/或 Cdc42 以及相关的细胞反应。我们将通过使用生化和细胞方法结合结构活性分析来测试这一假设，我们将测试是否存在化学信息学预测的 R-对映体选择性与 GTP 酶的 GDP 结合形式相互作用，从而导致 GTP 结合的阻断、酶激活和下游细胞反应。这项工作意义重大，因为 NSAID R 对映异构体的新颖药理学和肿瘤相关功能活性此前尚未被描述过，该项目的成功完成将为 NSAID 的抗癌益处提供新的机制见解。这些研究还将产生额外的成果 以及关于靶向 Rac1 和 Cdc42 在卵巢癌和其他癌症中的益处的重要信息。