Alain P Gobert1, Olivier Boutaud2, Mohammad Asim3, Irene A Zagol-Ikapitte4, Alberto G Delgado3, Yvonne L Latour5, Jordan L Finley3, Kshipra Singh6, Thomas G Verriere3, Margaret M Allaman3, Daniel P Barry3, Kara M McNamara3, Johanna C Sierra6, Venkataraman Amarnath7, Mohammed N Tantawy8, Diane Bimczok9, M Blanca Piazuelo6, M Kay Washington10, Shilin Zhao11, Lori A Coburn12, Keith T Wilson13. 1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: keith.wilson@vumc.org. 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: alain.p.gobert@vumc.org. 3. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 4. Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee. 5. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. 6. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee. 7. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee. 8. Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. 9. Department of Microbiology and Immunology, Montana State University, Bozeman, Montana. 10. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. 11. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. 12. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee. 13. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
Abstract
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (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: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, 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 in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium 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 intestinal metaplasia 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 as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. 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. Published by Elsevier Inc.
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (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: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, 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 in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium 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 intestinal metaplasia 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 as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. 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. Published by Elsevier Inc.
Entities:
Keywords:
Chemoprevention; Colorectal cancer; Electrophiles; Stomach Cancer
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