Growth arrest, apoptosis, and telomere shortening of Barrett's-associated adenocarcinoma cells by a telomerase inhibitor

Gastroenterology. 2004 May;126(5):1337-46. doi: 10.1053/j.gastro.2004.01.026.

Abstract

Background & aims: Barrett's esophageal adenocarcinoma (BEAC) is a complication of gastroesophageal reflux disease, with no effective chemotherapy and poor prognosis. BEAC cells, like many other types of cancers, may reactivate telomerase to achieve unlimited proliferative potential, making telomerase a unique therapeutic target. The purpose of this study was to evaluate effects of telomerase inhibition on BEAC.

Methods: We examined the effect of a selective G-quadruplex intercalating telomerase inhibitor, 2,6-bis[3-(N-Piperidino)propionamido]anthracene-9,10-dione (PPA), on telomerase activity, telomere length, colony size distribution, and proliferative potential in 2 BEAC cell lines, BIC-1 and SEG-1.

Results: Telomerase activity was >10-fold and >600-fold elevated in the adenocarcinoma cells as compared with normal gastric/intestinal cells and normal diploid fibroblasts, respectively. Telomeres were short, being less than 4 kilobase pair in both tumor cell lines. Exposure to PPA effectively inhibited telomerase activity and shortened telomeres. PPA also arrested cell proliferation and reduced colony number and size after a lag period of about 10 cell generations, consistent with the attrition of telomeres. The growth arrest was not due to senescence but was due to apoptosis. Expression analysis of the cells following PPA treatment did not show significant change in the expression of genes involved in cell-cycle proliferation and apoptosis. Exposure to PPA had no effect on proliferative potential of normal intestinal cells.

Conclusions: We conclude that telomerase inhibition by PPA induces cell growth arrest in BEAC cells and demonstrate the potential of telomerase inhibitors in chemoprevention and treatment of Barrett's-associated esophageal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / etiology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology*
  • Anthraquinones / pharmacology*
  • Apoptosis* / drug effects
  • Barrett Esophagus / complications*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology*
  • Esophageal Neoplasms / etiology
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / physiopathology*
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Humans
  • Piperidines / pharmacology*
  • Stem Cells / pathology
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism
  • Telomere / drug effects
  • Telomere / genetics*

Substances

  • 2,6-bis(3-(N-piperidino)propionamido)anthracene-9,10-dione
  • Anthraquinones
  • Enzyme Inhibitors
  • Piperidines
  • Telomerase