The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF- B activation in oesophageal cells, with a mechanism of action involving ROS

Abstract

Deoxycholic acid (DCA) is a secondary bile acid implicated in various cancers of the gastrointestinal (GI) tract. In oesophageal adenocarcinoma, DCA is believed to contribute to carcinogenesis during reflux where stomach contents enter the lower oesophagus. It is imperative that we understand the mechanisms whereby oesophageal carcinogens function in order that therapeutic options may be developed. We have previously shown that DCA can damage chromosomes and does so through its generation of reactive oxygen species (ROS). We show here, after detailed experiments, that DCA appears to have a non-linear dose response for DNA damage. DCA induces DNA damage (as measured by the micronucleus assay) at doses of 100 microM and higher in oesophageal OE33 cells, but fails to induce such DNA damage below this cut-off dose. We also show that in terms of NF-kappaB activation (as measured by up-regulation of two NF-kappaB target genes) by DCA, a similar dose response is observed. This dose-response data may be important clinically as DCA exposure to the oesophagus may be used as a way to identify the 10% of Barrett's oesophagus patients currently progressing to cancer from the 90% of patients who do not progress. Only quantitative studies measuring DCA concentrations in refluxates correlated with histological progression will answer this question. We further show here that ROS are behind DCAs ability to activate NF-kappaB as antioxidants (epigallocatechin gallate, resveratrol and vitamin C) abrogate DCAs ability to up-regulate NF-kappaB-controlled genes. In conclusion, low doses of DCA appear to be less biologically significant in vitro. If this were to be confirmed in vivo, it might suggest that reflux patients with low DCA concentrations may be at a lower risk of cancer progression compared to patients with high levels of DCA in their refluxate. Either way, antioxidant supplementation may possibly help prevent the deleterious effects of DCA in the whole GI tract.

Barrett’s to Oesophageal Cancer Sequence: A Model of Inflammatory-Driven Upper Gastrointestinal Cancer

“…In BO and OAC cell lines, bile acids induce increased ROS and increased cell proliferation in a complex system, possibly by induction of PI-PLCγ2, ERK2 MAP kinase, and NADPH oxidase NOX5-S via the TGR5 receptor [80,81]. Similar to findings in the colon, antioxidants such as reservatrol and vitamin C can block DCA-induced NF-κB expression [75], while people with high antioxidant intake have a 50% decreased risk of developing OAC compared with those with a low intake [82].…”

“…In Barrett's tissue, dysplasia is associated with increased oxidative DNA damage [72]. Bile acids can induce DNA damage via ROS production [73] and NF-κB activation [74][75][76] (another link to the inflammatory process), with increases in DNA double-strand breaks and intracellular ROS levels [77,78]. NO can increase invasiveness of dysplastic and cancerous cells via regulation of MMPs and TIMPs [79].…”

Evidence for Contributions of Gut Microbiota to Colorectal Carcinogenesis

“…Colonic mucosal proliferation has been associated positively with secondary bile acid levels [94]. In vitro studies have demonstrated the ability of secondary bile acids to up regulate NF-κβ expression and induce DNA damage through the generation of reactive oxygen species [95]. Bile salt hydrolases (BSHs) are crucial for bile acid modification by the gut microbiota.…”

A Favorable Response of Dysplastic Barrett’s Refractory to Ablation Therapy Only after Initiation of an Alginate Solution as Add-on Therapy

“…Bile acids have been shown to be damaging to esophageal epithelial cells by affecting membrane permeability, cell proliferation and differentiation, increasing free radicals, inducing DNA damage and up-regulating oncogenes [11,[14][15][16][17][18][19][20]. More specifically, both gastric acid and bile acids have been shown to activate NF-kappa B, a major molecule that is up-regulated in and intrinsic to cancer development.…”