Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

Abstract BACKGROUND & AIMS Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as iso-levuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response, and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS Formation of isoLG adducts was analyzed in gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia (IM), in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils, as models of H. pylori-induced carcinogenesis; and C57BL/6 mice treated with azoxymethane (AOM)-dextran sulfate sodium (DSS) as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H. pylori-infected INS-GAS mice was assessed by whole exome sequencing. RESULTS We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and IM, and in human gastric organoids infected with H. pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils, and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC, and in dysplastic tumors of C57BL/6 mice treated with AOM-DSS. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations, and are thus key targets for cancer chemoprevention.