pregna-4-17-diene-3-16-dione and Barrett-Esophagus

Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-κB (NF-κB) activation is a critical event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-κB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC.. Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of IκBα, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well.. GS inhibited DCA-induced IκBα phosphorylation. GS and the NF-κB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction.. GS suppressed DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Apoptosis; Barrett Esophagus; CDX2 Transcription Factor; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholagogues and Choleretics; Cyclooxygenase 2; Deoxycholic Acid; Dinoprostone; Drug Screening Assays, Antitumor; Esophageal Neoplasms; Homeodomain Proteins; Humans; I-kappa B Proteins; Neoplasm Proteins; NF-kappa B; Phosphorylation; Pregnenediones

Topics: Anticarcinogenic Agents; Apoptosis; Barrett Esophagus; Breast Neoplasms; Cell Proliferation; DNA-Binding Proteins; Humans; Melanoma; Pregnenediones; Receptors, Cytoplasmic and Nuclear; STAT3 Transcription Factor; Transcription Factors

Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function.. the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity. The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.. the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Apoptosis; Barrett Esophagus; Biopsy; Cell Culture Techniques; Cell Line, Tumor; DNA-Binding Proteins; Esophageal Neoplasms; Esophagitis, Peptic; Female; Gene Expression; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Immunohistochemistry; Male; Middle Aged; Precancerous Conditions; Pregnenediones; Receptors, Calcitriol; Receptors, Cytoplasmic and Nuclear; Transcription Factors