Prevention of genomic instability by a scavenger of bifunctional electrophiles

双功能亲电试剂清除剂预防基因组不稳定性

基本信息

批准号：
9186510
负责人：
JOHN Alexander OATES
金额：
$ 20.4万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186510
关键词：
Address Adenine Aldehydes Alleles Amination Amines Animals Bacteria Barrett Esophagus Cancer cell line Carcinogens Cell Nucleus Cells Cessation of life Colon Carcinoma Copy Number Polymorphism Cysteine DNA DNA Adducts DNA Modification Process Development Epigenetic Process Evaluation Event FVB Mouse Genetic Recombination Genomic Instability Genomics Genotype Histology Histones Human Hydrogen Isomerism KRAS2 gene Lesion Lipid Peroxidation Lipid Peroxides Lipoxygenase Lung Lysine Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malondialdehyde Mammalian Cell Mediating Metabolism Mouse Strains Mus Mutagens Mutation N-methylacetamide-oxotremorine M Nature Nuclear Nucleic Acids Nucleoproteins Nucleosides Oncogenic Oxidants PTGS2 gene Patients Penetrance Periodicity Positioning Attribute Post-Translational Protein Processing Premalignant Prevention Process Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Isoforms Proteins Rattus Research Series Site Structure System Testing Thromboxane A2 Thromboxanes adduct analog base clinically significant crosslink cyclooxygenase 2 cytotoxic early onset histone modification in vivo ketoaldehyde macromolecule malignant breast neoplasm malignant phenotype mouse model oxidation prevent public health relevance tool tumor

项目摘要

DESCRIPTION (provided by applicant): Progression from pre-malignant lesions to clinically significant cancers involves acquisition of somatic genomic abnormalities that in concert drive the development of cancers with a highly malignant phenotype. Reactive dicarbonyls derived from cyclooxygenase-2 (COX-2), the lipoxygenases and lipid peroxidation are known to form covalent adducts of DNA and histones. It is proposed to address the hypothesis that these modifications of DNA and histones contribute to the somatic genomic abnormalities that characterize cancers. The immediate product of both COX isoforms is the cyclic endoperoxide, prostaglandin H2 (PGH2), the substrate for the synthases that produce the prostaglandins and thromboxane A2. PGH2 also undergoes non-catalytic rearrangement to form the levuglandins, highly reactive γ-ketoaldehydes. In cancer cell lines, we have demonstrated that COX-2 derived levuglandins form covalent adducts of DNA and histones. Our group has investigated a series of scavengers of levuglandins that react with these 1,4-dicarbonyls at a rate 3 orders of magnitude faster than does lysine, thereby inhibiting the formation of the levuglandin adducts of cellular amines on DNA bases and on histones. We have identified one, 5-ethylsalicylamine that is potent in preventing levuglandin adducts of lysine, does not inhibit COX-2 and acts in the cellular nucleus. Importantly, we discovered that 5-ethylsalicylamine is a general scavenger of reactive dicarbonyls, including malondialdehyde and 4-oxo-nonenal, both of which also form covalent adducts of DNA. To evaluate the hypothesis that these reactive dicarbonyls are endogenous carcinogens, we will determine the effects of 5- ethylsalicylamine on the development of the somatic genomic abnormalities that occur in a mouse with lung expression of a Kras mutation that produces lung cancers which progressively develop genomic instability with extensive copy number variations. Copy number variations will be determined with the Mouse Diversity Genotyping Array. The effect of 5-ethylsalicylamine on tumor size and histology also will be evaluated as well as its effect on the levels of levuglandin and malondialdehyde adducts of DNA and histones in the tumors. In summary, a number of reactive dicarbonyls, exemplified by the levuglandins, malondialdehyde and 4-oxo- nonenal, are produced by COX-2, lipid peroxidation and the lipoxygenases and can form covalent adducts of DNA and histone, suggesting that they could be endogenous carcinogens. It is hypothesized that 5- ethylsalicylamine, a scavenger of these dicarbonyls, will prevent the genomic instability that occurs in a mouse model of lung cancer.

描述（由申请人提供）：从癌前病变进展为具有临床意义的癌症涉及体细胞基因组异常的获得，这些异常共同驱动源自环氧合酶-2（COX-2）的高度恶性表型的癌症的发展。已知脂氧合酶和脂质过氧化作用可形成 DNA 和组蛋白的共价加合物，提出了 DNA 和组蛋白的这些修饰的假设。组蛋白导致体细胞基因组异常，这两种 COX 亚型的直接产物是环内过氧化物前列腺素 H2 (PGH2)，它是产生前列腺素和血栓素 A2 的合成酶的底物，也会发生非催化重排。在癌细胞系中形成 levuglandins，高反应性 γ-酮醛，我们已经证明 COX-2 衍生。我们小组研究了一系列 levuglandin 清除剂，它们与这些 1,4-二羰基的反应速度比赖氨酸快 3 个数量级，从而抑制细胞中 levuglandin 加合物的形成。我们已经鉴定出一种 5-乙基水杨胺，可以有效预防 levuglandin。重要的是，5-乙基水杨胺是赖氨酸的加合物，不抑制 COX-2 并在细胞核中起作用，重要的是，我们发现 5-乙基水杨胺是活性二羰基的通用清除剂，包括丙二醛和 4-氧代壬烯醛，这两种物质也形成赖氨酸的共价加合物。 DNA。为了评估这些反应性二羰基是内源性致癌物的假设，我们将确定 5-乙基水杨胺的影响。肺部表达 Kras 突变的小鼠中发生的体细胞基因组异常的发展会逐渐发展出具有广泛拷贝数变异的基因组不稳定性，这将通过小鼠多样性基因分型阵列来确定。还将评估 5-乙基水杨胺对肿瘤大小和组织学的影响，以及它对肿瘤细胞中 levuglandin 和 DNA 和组蛋白的丙二醛加合物水平的影响。总之，许多反应性二羰基化合物，例如左旋糖兰素、丙二醛和 4-氧代壬烯醛，是由 COX-2、脂质过氧化和脂氧合酶产生的，并且可以形成 DNA 和组蛋白的共价加合物，表明它们可能是内源性的。人们再次认识到，5-乙基水杨胺是这些二羰基化合物的清除剂，可以预防致癌物质。肺癌小鼠模型中出现的基因组不稳定性。