Prevention of genomic instability by a scavenger of bifunctional electrophiles

Vanderbilt University, Nashville TN

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Abstract

? 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 ?-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.