title: Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts.
abstract: Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA.|Department of Surgery.
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhardwaj
authors.affiliation: Department of Surgery.
authors.forename: Andela
authors.initials: A
authors.lastname: Horvat
authors.affiliation: Department of Surgery.
authors.forename: Olga
authors.initials: O
authors.lastname: Korolkova
authors.affiliation: Department of Cancer Biology and.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Surgery.|Department of Cancer Biology and.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Dikalov
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA, alex.zaika@vanderbilt.edu.|Department of Surgery.|Department of Cancer Biology and.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Zaika
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000143:Acids / Q000009:adverse effects; D000230:Adenocarcinoma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000975:Antioxidants / Q000008:administration & dosage; D019313:BRCA1 Protein / Q000096:biosynthesis; D001471:Barrett Esophagus / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001647:Bile Acids and Salts / Q000009:adverse effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000143:Acids; D000975:Antioxidants; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001647:Bile Acids and Salts; D017382:Reactive Oxygen Species; C056165:acetovanillone