Signal Transduction Enzyme Inhibitors from Extremophilic Microbes as Anticancer A

嗜极微生物信号转导酶抑制剂作为抗癌 A

• 批准号: 8052902
• 负责人: ANDREA Anne STIERLE
• 金额: $ 20.97万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052902
• 关键词: Acids; Address; Adverse effects; American; Antineoplastic Agents; Area; Biological Assay; Biological Factors; Biomedical Research; Cancer cell line; Caspase-1; Cause of Death; Cell Line; Cytotoxic agent; Developmental Therapeutics Program; Diagnosis; Environment; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Exhibits; Fermentation; Funding; Goals; Health; Human; Inorganic Sulfates; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Metals; Methodology; Microbe; Mining; Modality; National Cancer Institute; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organism; Public Health; Research; Research Institute; Scheme; Signal Transduction; Source; Stromelysin 1; Structure; Students; Techniques; Testing; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Water; Western World; anticancer activity; base; cancer type; cytotoxicity; drug discovery; in vitro activity; leukemia; meetings; microbial; microorganism; novel; novel strategies; programs; success; tool; wasting

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery of new natural products with anticancer activity from extremophilic microbes isolated from an acid mine waste lake. Compounds will be isolated based on their ability to inhibit specific signal transduction enzymes that have been implicated in the onset and metastasis of several different types of cancer. Matrix metalloproteinase-3 (MMP-3) and caspase-1 (casp-1) have been shown to be up-regulated in certain cancers. For the past five years we have developed a bioassay-guided isolation scheme that has resulted in the isolation and purification of several novel compounds that inhibit one or both of these enzymes. The structures of these compounds were elucidated through spectral techniques. To establish a correlation between enzyme inhibition and anticancer activity, these pure enzyme inhibitors were submitted to the National Cancer Institute Developmental Therapy Program (NCI/DTP) for testing against 60 human cancer cell lines. This methodology has resulted in the isolation and identification of several lead compounds with nanomolar or low micromolar activity and high selectivity towards ovarian cancer, non-small cell lung cancer, and leukemia. Microbes isolated from acid mine waste have proven to be a rich source of previously unreported, bioactive metabolites. Preliminary studies, which have been funded through the National Institutes of Health-IDeA Networks of Biomedical Research Excellence (INBRE), yielded over 70 different microorganisms from the metal sulfate rich waters and deep basal sediment. Of the 30 microorganisms already examined in small pilot fermentation studies, over 50% of the extracts inhibited MMP-3 and/or Casp-1. In- depth exploration of five of these organisms has yielded several novel compounds including berkelic acid, which exhibited selective nanomolar activity against OVCAR-3 and berkeleydione which exhibited selective low micromolar activity against nonsmall cell lung cancer strain NCI-H460. With these early successes we would like to continue studying these microbes with the following specific aims: 1. Isolate compounds from targeted extremophilic microorganisms using signal transduction enzyme inhibition as an isolation guide. 2. Elucidate the structures of these compounds using spectroscopic or x-ray methodology. 3. Test active compounds in the NIH/DTP cell line screen to determine in vitro activity. 4. Send compounds with enzyme inhibitory activity and nanomolar - low micromolar activity against specific human cancer cell lines to Eisai Research Institute for further evaluation. 5. Involve undergraduate students in all aspects of microbial drug discovery This research has shown promise and the funds requested for this RO1 would be used to continue this exploration. It addresses a critical need area and combines both unique assay tools and a unique extreme environment for drug discovery. PUBLIC HEALTH RELEVANCE: Over 565,000 Americans are expected to die of cancer this year, and more than 2,437,000 new cancer cases are expected to be diagnosed. Despite our arsenal of anticancer agents, cancer is now the second leading cause of death in the western world. Unfortunately, current treatment modalities use cytotoxic agents that can cause deleterious side-effects. This application describes a novel approach to drug discovery, using signal transduction enzyme inhibition as a guide to the isolation of selective, potent anticancer agents from extremophilic microbes. Enzyme inhibitors will be tested by NCI/DTP against 60 human cancer cell lines and by Eisai Research Institute to determine anticancer activity. Novel compounds will help meet the increasing need for new treatment modalities with high selectivity and potency, and lower cytotoxicity than current treatment options.

描述（由申请人提供）：该项目的总体目标是发现了从酸性矿物废物湖中分离出的极端微生物的抗癌活性的新天然产品。化合物将根据其抑制与几种不同类型癌症的发作和转移有关的特定信号转导酶的能力进行分离。基质金属蛋白酶-3（MMP-3）和caspase-1（CASP-1）已显示在某些癌症中已上调。在过去的五年中，我们开发了一种生物测定指导的隔离方案，该方案导致了几种抑制一种或两种这些酶的新型化合物的隔离和纯化。这些化合物的结构通过光谱技术阐明了。为了在酶抑制和抗癌活性之间建立相关性，将这些纯酶抑制剂提交给国家癌症研究所发展疗法计划（NCI/DTP），以针对60种人类癌细胞系进行测试。这种方法导致对纳摩尔或低微摩尔活性或对卵巢癌，非小细胞肺癌和白血病的几种铅化合物的分离和鉴定。从酸性矿物废物中分离出来的微生物已被证明是先前未报告的生物活性代谢物的丰富来源。初步研究是通过国立生物医学研究卓越的国家健康研究所网络（INBRE）资助的，从金属富含硫酸盐富含金属的水和深层沉积物中产生了70多种不同的微生物。在小型试点发酵研究中已经检查的30种微生物中，超过50％的提取物抑制了MMP-3和/或CASP-1。对其中五种生物的深度探索产生了几种新型化合物，包括贝尔克酸，它们对OVCAR-3和Berkeleydione表现出选择性的纳摩尔活性，这些活性表现出对非小细胞肺癌菌株NCI-H460的选择性低微压活性。通过这些早期的成功，我们希望继续以以下特定目的研究这些微生物：1。使用信号转导酶抑制作为隔离指南的靶向极性微生物分离物。 2。使用光谱或X射线方法阐明这些化合物的结构。 3。在NIH/DTP细胞线筛选中测试活性化合物以确定体外活性。 4。将具有酶抑制活性的化合物和纳摩尔 - 微摩尔活性针对特定的人类癌细胞系的纳摩尔活性向EISAI研究所进行进一步评估。 5。让本科生参与微生物药物发现的各个方面，这项研究表明了有望，并要求该RO1的资金将用于继续此次探索。它解决了关键的需求领域，并结合了独特的测定工具和吸毒的独特极端环境。公共卫生相关性：预计今年有超过56.5万名美国人死于癌症，预计将诊断出超过2,437,000例新的癌症病例。尽管我们是抗癌药的武器库，但癌症现在是西方世界中第二大死亡原因。不幸的是，当前的治疗方式使用可引起有害副作用的细胞毒性剂。该应用描述了一种新型的药物发现方法，使用信号转导酶抑制作用，作为从极端微生物中选择性，有效的抗癌剂分离的指南。 NCI/DTP将对60种人类癌细胞系和EISAI研究所测试酶抑制剂，以确定抗癌活性。与目前的治疗方案相比，新型化合物将有助于满足具有高选择性和效力的新治疗方式的需求，而细胞毒性较低。