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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：来自放线菌和其他细菌的发酵衍生的天然产物是药物发现的重要组成部分，启发了50％的临床认可药物，被证明是癌症研究中的宝贵工具。天然产品通常会有效地发挥作用并表现出很高的特异性 - 使其可用于与癌症有关的探测信号通路。因此，继续努力识别具有与人类癌症相关的有效生物学活动的新天然产品是一项重要的努力。该项目的目的是确定可以成为开发新型癌症治疗剂或生化探针的新天然产品。将微生物学，天然产品化学和与癌症生物学专家合作结合的多方面方法将用于实现这一目标。具体而言，我们建议通过利用诸如pH，PO2和化学信号传导等环境因素来开发新的经验和生化技术，从海洋栖息地培养放线菌。人们普遍认为，只有一小部分细菌是可以培养的，因此需要新的二级代谢物生成细菌的技术。海洋细菌的收集将是建立自然产品分数库进行生物学筛查工作的基础。我们将使用基于生物化学的靶标测定，基于细胞的表型测定和选择性的细胞毒性研究的组合来鉴定与信号转导途径相互作用的分子（例如，凋亡，坏死，Wnt/？ - 蛋白蛋白，HIF），并调节诸如DNA甲基替代酶的DNA甲基替代酶。一个特定生物学靶标的例子，我们将利用基于细胞的测定方法来发现使用Wnt响应性细胞系在Wnt途径中特别相互作用的分子，这在大量癌症中很重要（最著名的是90％的结肠癌）。为了适应提出的大量生物测定中主动命中的化学评估，我们将基于LC-SPE-NMR技术开发分析化学技术，以快速定量和定性分析。最后，我们将使用传统的天然产品化学技术来表征我们在生物学筛查中鉴定的新次生代谢产物。