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（通过应用程序提供）：从恶性病变到临床意义的癌症的进展涉及恢复体细胞基因组异常，这些异常会促进具有高度恶性表型的癌症的发展。已知源自环氧合酶-2（COX-2），脂氧酶和脂质过氧化的反应性二苯子已知形成DNA和组蛋白的共价加合物。提议解决以下假设：DNA和组蛋白的这些修饰有助于表征癌症的体细胞基因组异常。两种Cox同工型的直接产物是环氧化物前氧化物，前列腺素H2（PGH2），这是产生前列腺素和血栓烷A2的合成酶的底物。 PGH2还经历了非催化重排以形成左旋甘油素，高反应性γ-酮醛。在癌细胞系中，我们已经证明了Cox-2衍生的左甘油素形成了DNA和组蛋白的共价加合物。我们的小组已经调查了一系列左瓜素蛋白的清除剂，这些清除剂与这1,4-二甲苯子的反应速度要比赖氨酸快3个数量级，从而抑制了DNA碱基和组蛋白上细胞胺的列伏兰蛋白加合物的形成。我们已经确定了一种潜在的5-乙基氨基酰胺，可以预防赖氨酸的左旋兰蛋白加合物，并没有抑制COX-2的重要性，我们发现5-乙基盐酸氨是对反应性二甲苯的普遍清除剂，其中包括包括malondehyde和4-oxo-oxo-nonenenal，这两种形式的covaln and covalent covaln and covaln no。为了评估这些反应性二苯子是内源性致癌物的假设，我们将确定5-乙基水杨胺对在肺癌中产生肺癌的肺表达中发生的小鼠中发生的体细胞基因组异常的影响，从而逐渐发展出具有广泛的副本拷贝数量的肺癌。拷贝数变化将用小鼠多样性基因分型阵列确定。还将评估5-乙基白杨氨对肿瘤大小和组织学的影响，以及它对肿瘤中DNA和组蛋白的左瓜素蛋白和丙二醛加合物水平的影响。总而言之，由Levuglandins，Malondiarydehyde和4-氧化的非反应性二苯丙基由Cox-2，脂质过氧化和脂氧酶产生，并可以形成DNA和组蛋白的共同加成，这表明它们可能是核激素的。假设5-乙基氨基胺是对这些双骨的清真寺的，将防止在肺癌小鼠模型中发生的基因组不稳定性。