Marine Actinomycetes as a Resource for Anticancer Natural Products

海洋放线菌作为抗癌天然产品的资源

• 批准号: 8462118
• 负责人: JOHN B MACMILLAN
• 金额: $ 30.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462118
• 关键词: Actinobacteria class; Analytical Chemistry; Antineoplastic Agents; Apoptosis; Bacteria; Biochemical; Biochemistry; Biological; Biological Assay; Biological Factors; Biomedical Research; Cancer Biology; Cell Line; Cells; Cellular biology; Chemicals; Chemistry; Chromatography; Collaborations; Collection; Colon Carcinoma; Complex Mixtures; Cytotoxic agent; DNA Methyltransferase; DNA Modification Methylases; Development; Discipline; Environment; Environmental Risk Factor; Epigenetic Process; Evaluation; Exhibits; FDA approved; Fermentation; Foundations; Generations; Germination; Goals; Habitats; Histone Deacetylase; Human; Lead; Libraries; Malignant Neoplasms; Marines; Mass Spectrum Analysis; Methodology; Microbiology; Molecular; Natural Products Chemistry; Necrosis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Plant Resins; Property; Research; Resources; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solid; Specificity; Structure; Techniques; Technology; Therapeutic; Translational Research; Tumor Cell Line; X-Ray Crystallography; analytical method; anticancer research; base; cancer therapy; cellular targeting; cytotoxic; cytotoxicity; drug discovery; high throughput screening; insight; microbial; microorganism; novel; oncology; programs; public health relevance; quorum sensing; rapid technique; reversed phase chromatography; screening; small molecule; tool; tumor

DESCRIPTION (provided by applicant): Fermentation derived natural products from actinomycetes and other bacteria have been an important component of drug discovery inspiring 50% of clinically approved drugs and proven to be invaluable tools in cancer research. Natural products often exert their effects potently and exhibit high specificity - making them useful to probe signaling pathways related to cancer. As such, a continued effort to identify new natural products with potent biological activity relevant to human cancers is an important endeavor. The goal of this project is to identify new natural products that can be lead structures for the development of novel cancer therapeutics or biochemical probes. A multi-faceted approach that combines microbiology, natural products chemistry and collaboration with experts in cancer biology will be used to accomplish this goal. Specifically, we propose to develop new empirical and biochemical techniques to culture actinomycetes from marine habitats, by taking advantage of environmental factors such as pH, pO2 and chemical signaling. As it is widely believed that only a small percentage of bacteria are culturable, new techniques to isolate secondary metabolite producing bacteria are necessary. The collection of marine bacteria will serve as the foundation to build a natural product fraction library for biological screening efforts. We will use a combination of biochemical target-based assays, cell-based phenotypic assays and selective cytotoxicity studies to identify molecules that interact with signal transduction pathways (eg. apoptosis, necrosis, Wnt/?-catenin, HIF) and modulate epigenetic factors such as DNA methyltransferase and histone deacetylase. An example of a specific biological target, we will utilize a cell-based assay to discover molecules that interact specifically in the Wnt pathway using a Wnt responsive cell line, which is important in large number of cancers (most notably up to 90% of colon cancer). To accommodate the chemical evaluation of active hits in the large number of bioassays proposed, we will develop analytical chemistry techniques based on LC-SPE-NMR technology for rapid quantitative and qualitative analysis. Finally, we will use traditional natural products chemistry techniques to characterize new secondary metabolites that we identify in our biological screening.

描述(申请人提供)：从放线菌和其他细菌中提取的发酵天然产物一直是药物发现的重要组成部分，激励了50%的临床批准药物，并被证明是癌症研究的无价工具。天然产物往往发挥其强大的作用，并表现出高度的特异性-使它们有助于探索与癌症相关的信号通路。因此，继续努力寻找与人类癌症相关的具有强大生物活性的新天然产物是一项重要的努力。该项目的目标是确定新的天然产品，这些产品可以作为开发新的癌症疗法或生化探针的先导结构。将使用结合微生物学、天然产品化学以及与癌症生物学专家合作的多方面方法来实现这一目标。具体地说，我们建议开发新的经验和生化技术来培养海洋生境中的放线菌，利用环境因素，如pH，pO2和化学信号。由于人们普遍认为只有一小部分细菌是可培养的，因此有必要采用新的技术来分离产生次生代谢物的细菌。海洋细菌的收集将作为建立天然产品组分库的基础，用于生物筛选工作。我们将结合基于生化靶标的分析、基于细胞的表型分析和选择性细胞毒性研究来确定与信号转导途径相互作用的分子(例如。凋亡、坏死、Wnt/β-连环蛋白、HIF)，并调节表观遗传因子，如DNA甲基转移酶和组蛋白脱乙酰酶。作为特定生物靶点的一个例子，我们将利用基于细胞的分析，使用Wnt反应细胞系来发现在Wnt途径中特定相互作用的分子，这在许多癌症(最明显的是高达90%的结肠癌)中是重要的。为了适应大量生物测试中对活性HITS的化学评估，我们将开发基于LC-SPE-核磁共振技术的分析化学技术，以实现快速的定量和定性分析。最后，我们将使用传统的天然产物化学技术来表征我们在生物筛选中确定的新的次生代谢物。