Anticancer Agents from Plant- and Lichen-Associated Fungi of the Sonoran Desert

索诺兰沙漠植物和地衣相关真菌的抗癌剂

基本信息

批准号：
8193083
负责人：
LESLIE GUNATILAKA
金额：
$ 26.35万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-04 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193083
关键词：
Acidosis Affinity American Angiogenesis Inhibitors Antineoplastic Agents Binding Biochemical Biological Biological Assay Biological Factors Biology Blood capillaries Buffers Cancer Patient Cancer cell line Cell Adhesion Cell Movement Process Cell Proliferation Cell Shape Cell Survival Cells Characteristics Chemicals Clinical Trials Collection Consensus Conventional Surgery Culture Media Cytotoxic agent Databases Development Disseminated Malignant Neoplasm Dyes Elements Endothelial Cells Environment Evaluation Event Exhibits Exposure to Extracellular Matrix Fractionation Funding Gene Expression Gene Expression Profiling Genes Genetic Genomics Genotype Goals Grant Growth Health Heat shock proteins Heat-Shock Response Heating Heavy Metals Homeostasis Human Hypoxia Indium Institutes Intervention Lead Lesion Libraries Lichen - organism Life Literature Luciferases MCF7 cell Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Molecular Molecular Chaperones Molecular Mechanisms of Action Molecular Target Mutation Neoplasm Metastasis Organism Outcome Pattern Phenotype Plants Play Precipitation Procedures Process Production Progress Reports Proteins Proteome Proteomics Public Health Relative (related person)Reporter Reporting Research Resources Role Screening procedure Sentinel Signaling Molecule Solid Neoplasm Source Taxonomy Techniques Therapeutic Tissues Tumor Cell Invasion Vascularization Work angiogenesis antiangiogenesis therapy anticancer activity base cancer cell cancer therapy capillary cell motility cell type chaperone machinery chemotherapy conventional therapy cytotoxic cytotoxicity design drug discovery fumagillin fungus inhibitor/antagonist innovation insight interest malignant breast neoplasm microbial migration neoplastic cell novel prevent protein folding response scale up small molecule stress protein stressor success tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Natural products have made enormous contributions to human health. The search for new lead compounds from natural sources continues to be a crucial element in modern anticancer drug discovery. Our long-term goal is to discover anticancer drugs that act by novel mechanisms from plant- and lichen-associated fungi of the Sonoran desert, thereby providing further support for our hypothesis that organisms living in association with one another in this unique environment elaborate a relatively unexplored repertoire of potent bioactive compounds with which to mediate their interactions and enhance their survival. The specific aims of this interdisciplinary and inter-institutional project are to: 1. expand our unique bio-resource of Sonoran desert plant- and lichen-associated fungi and optimize biosynthetic potential of 500 selected fungal strains and prepare 2,500 extracts for evaluation; 2. screen extracts for anticancer activity using cell-based biological and molecular approaches including: (a) an assay established during our previous grant period and recently modified to detect compounds capable of heat shock induction and inhibition of heat shock induction, followed by assays for direct interaction with Hsp90 including luciferase-refolding and binding assays for compounds isolated using the heat shock induction assay; (c) an assay for inhibitors of cell motility at sub-cytotoxic concentrations, and (d) a conventional dye reduction assay for inhibition of proliferation/survival based on five sentinel cancer cell lines to avoid the discovery of general cytotoxic agents; 3. dereplicate active extracts, culture on large-scale up to five promising fungal strains per year and subject their extracts to bioassay-guided fractionation to isolate and characterize bioactive compounds; and 4. define molecular mechanisms of action using genomic and proteomic approaches for the most promising compounds based on their activity, structural novelty, and potency. We expect that the most interesting compounds will serve as leads for further optimization in the development of novel anticancer agents with unique mechanisms of action. At a more basic scientific level, however, the innovative chemical biology approach we propose should help define the mechanisms by which (a) chaperones such as Hsp90 facilitate oncogenesis, and (b) small-molecules inhibit cancer cell migration involved in invasion and metastasis, leading to enhancement of our overall ability to prevent and cure cancers, and therefore have a great impact on public health. PUBLIC HEALTH RELEVANCE: This project proposes to discover anticancer drugs that act by novel mechanisms from hitherto unexploited natural sources, the outcome of which will lead to enhancement of our overall ability to prevent and cure cancers, and therefore have a great impact on public health.

描述（由申请人提供）：天然产品为人类健康做出了巨大贡献。从天然来源寻找新的铅化合物的搜索仍然是现代抗癌药物发现中的关键因素。我们的长期目标是发现通过植物和地衣相关的索诺兰沙漠真菌的新型机制起作用的抗癌药物，从而为我们的假设提供了进一步的支持，即我们在这种独特的环境中相互生活的有机体培养了一种相对未经探索的有效的生物活性复合曲目，以使他们的互动与他们的互动相互作用并增强他们的互动并增强他们的互动。这个跨学科和机构间项目的具体目的是：1。扩展我们独特的索诺兰沙漠植物和地衣相关的真菌的生物资源，并优化了500种选定的真菌菌株的生物合成潜力，并准备2,500种提取物进行评估； 2。使用基于细胞的生物学和分子方法进行抗癌活性的筛查提取物，包括：（a）在我们上次赠款期间建立的测定法，最近对检测能够诱导热休克诱导和抑制热休克诱导的化合物进行了修改，然后测定与HSP90直接相互作用的HSP90相互作用，包括使用Luciferase-Refoldase-Refoldose-Reflose-Reflose-Reflass-Reflass-Reflase Assounds使用该高热震动的震动，用于隔离热量，并隔离热量。（c）基于五个前哨癌细胞系的抑制剂抑制细胞运动抑制剂的抑制剂，以及（d）传统的染料降低测定法，以抑制增殖/生存率，以避免发现一般的细胞毒性剂； 3。消除活跃的提取物，每年最多五种有前途的真菌菌株对大规模培养，并将其提取物对生物测定引导的分馏进行隔离和表征生物活性化合物； 4。使用基于其活性，结构新颖性和效力的最有希望的化合物来定义分子机制，以使用基因组和蛋白质组学方法来定义作用机制。我们预计，最有趣的化合物将作为具有独特作用机理的新型抗癌剂的进一步优化的铅。然而，在更基本的科学层面上，我们提出的创新化学生物学方法应有助于定义（a）诸如HSP90之类的伴侣的伴侣促进肿瘤发生的机制，以及（b）小分子抑制癌细胞迁移涉及入侵和转移的癌细胞迁移，从而增强了我们的整体预防能力，从而增强了公众的整体影响，从而对公众产生了很大的影响，从而对癌症的健康产生了很大的影响。公共卫生相关性：该项目提议发现抗癌药通过迄今未开发的自然来源的新机制起作用，其结果将导致我们预防和治愈癌症的整体能力增强，从而对公共卫生产生重大影响。