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: 8625502
• 负责人: LAURIE G HUDSON
• 金额: $ 5万
• 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/8625502
• 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挑战我们确定通常用于其他适应症的药物，例如抗炎药（NSAID），可以预防癌症的发病率和死亡率”。强有力的初步数据导致我们提出，对于某些化学实体，化学预防和/或抗肿瘤活性归因于精选NSAID的R-Enantiomer与Select NSAID与 新型癌症 - 相关靶标。有许多在药物活性上立体选择性差异的例子。非类固醇抗炎药（NSAIDS）的R形式基本上是对环氧酶的非活性，并且有越来越多的证据表明，R-Enantiomers是具有独立药理活性的不同化学实体。我们发现，萘普生和酮洛克拉克的R-替代体抑制了小的GTPases Rac1和cdc42。其他20多种NSAID对这些蛋白质无活性，这表明R-Naproxen和R-Ketorolac的新靶选择性。 RAC1和CDC42除了其他功能外，还调节细胞骨架动力学，并且被认为是有吸引力的癌症治疗靶标，尽管目前尚无特定抑制剂在临床试验中。为了与RAC1/CDC42在调节基于肌动蛋白的功能中的已知功能保持一致，我们发现映体选择性抑制卵巢肿瘤细胞迁移和粘附。此外，R-Naproxen，但不是S-Naproxen或与结构相关的6-甲氧基萘乙酸（6 mNA），在腹膜内异种移植模型中降低了卵巢肿瘤的植入约75％。该应用的目的是定义R-Naproxen和R-Ketorolac观察到的生物学活性的作用机理。这将为基础，以基于与新目标的相互作用来重新考虑其他NSAID R-Enantiomers的潜在抗肿瘤活性。我们假设R-Ketorolac和R-Naproxen通过基于药物结合与GDP结合（不活跃）酶的新机制抑制RAC1和/或CDC42以及相关的细胞反应。我们将通过使用与结构活性分析的生化和细胞方法来检验该假设，我们将测试是否与GDP结合的GDP酶的R-替代异构体选择性相互作用，如化学形式所预测的，从而导致GTP结合，enzyme Enzyme活化活化和下流细胞响应的封锁。这项工作之所以重要，是因为NSAID R-Enantiomers的新型药理学和与肿瘤相关的功能活动尚未被描述，并且该项目的成功完成将为NSAID的抗癌益处提供新的机械见解。研究还将产生更多 以及有关靶向Rac1和CDC42在卵巢和其他癌症中的好处的关键信息。