Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts

Carcinogenesis. 2016 Dec;37(12):1161-1169. doi: 10.1093/carcin/bgw100. Epub 2016 Sep 21.


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.

MeSH terms

  • Acetophenones / administration & dosage*
  • Acids / adverse effects
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / etiology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Antioxidants / administration & dosage
  • BRCA1 Protein / biosynthesis
  • Barrett Esophagus / drug therapy
  • Barrett Esophagus / etiology
  • Barrett Esophagus / metabolism*
  • Barrett Esophagus / pathology
  • Bile Acids and Salts / adverse effects
  • Bile Acids and Salts / metabolism
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • Esophageal Neoplasms / drug therapy
  • Esophageal Neoplasms / etiology
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / pathology
  • Gastric Acid / metabolism
  • Gastroesophageal Reflux / complications
  • Gastroesophageal Reflux / metabolism*
  • Gastroesophageal Reflux / pathology
  • Humans
  • Reactive Oxygen Species / metabolism


  • Acetophenones
  • Acids
  • Antioxidants
  • BRCA1 Protein
  • BRCA1 protein, human
  • Bile Acids and Salts
  • Reactive Oxygen Species
  • acetovanillone

Supplementary concepts

  • Adenocarcinoma Of Esophagus