The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: An in vitro study

Navtej Singh Buttar, Kenneth Ke Ning Wang, Marlys A. Anderson, Ross A. Dierkhising, Rodney J. Pacifico, Krishnawatie K. Krishnadath, L. S. Lutzke

Research output: Contribution to journalArticle

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Abstract

Background: Individuals with Barrett's esophagus, in which the normal squamous esophageal epithelium is replaced with a columnar mucosa, are at increased risk for esophageal adenocarcinoma. Mucosal injury may be involved in the progression to neoplasia via the synthesis of prostaglandins and other mediators of inflammation. Cyclooxygenase (COX)-2 is the rate-limiting enzyme involved in prostaglandin synthesis. We examined the effect of inhibiting COX-2 activity in Barrett's esophageal cells. Methods: Primary esophageal epithelial and fibroblast cell cultures were established from endoscopic biopsy specimens from 20 consecutive patients with Barrett's esophagus. COX-2 expression and activity were determined on pooled cell cultures by reverse transcription-polymerase chain reaction and prostaglandin E2 (PGE2) enzyme immunoassay, respectively. Proliferation was measured by Ki-67 staining. PGE2 levels were determined in supernatants from epithelial cells treated with the selective COX-2 inhibitor NS-398, proinflammatory cytokines (interleukin 1β and tumor necrosis factor-α), and conditioned medium from fibroblast cultures (both unstimulated and stimulated with proinflammatory cytokines). Results: Esophageal epithelial cells and fibroblasts expressed COX-2 messenger RNA. Compared with control-treated cells, NS-398 decreased proliferation of Barrett's esophageal epithelial cells by 55% (95% confidence interval = 47.1% to 63.8%; P<.001) and decreased COX-2 activity. The addition of exogenous PGE2 reversed the antiproliferative effect of NS-398 on Barrett's esophageal epithelial cells. Proinflammatory cytokines did not affect COX-2 activity in esophageal epithelial cells but stimulated COX-2 activity in fibroblasts. However, conditioned medium from unstimulated and stimulated fibroblasts increased COX-2 activity in esophageal epithelial cells. Conclusion: COX-2 is functionally active in Barrett's esophagus because treatment with the COX-2 inhibitor hinders proliferation of Barrett's esophageal epithelial cells in culture, but proliferation is restored by treatment with prostaglandin. These results raise the possibility that inhibition of COX-2 may have chemopreventive potential for Barrett's esophagus.

Original languageEnglish (US)
Pages (from-to)422-429
Number of pages8
JournalJournal of the National Cancer Institute
Volume94
Issue number6
StatePublished - Mar 20 2002

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Barrett Esophagus
Cyclooxygenase 2
Epithelial Cells
Fibroblasts
Dinoprostone
Prostaglandins
Cell Culture Techniques
Cyclooxygenase 2 Inhibitors
Conditioned Culture Medium
Cytokines
In Vitro Techniques
Inflammation Mediators
Immunoenzyme Techniques
Interleukin-1
Reverse Transcription
Mucous Membrane
Adenocarcinoma
Epithelium
Tumor Necrosis Factor-alpha
Confidence Intervals

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Buttar, N. S., Wang, K. K. N., Anderson, M. A., Dierkhising, R. A., Pacifico, R. J., Krishnadath, K. K., & Lutzke, L. S. (2002). The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: An in vitro study. Journal of the National Cancer Institute, 94(6), 422-429.

The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium : An in vitro study. / Buttar, Navtej Singh; Wang, Kenneth Ke Ning; Anderson, Marlys A.; Dierkhising, Ross A.; Pacifico, Rodney J.; Krishnadath, Krishnawatie K.; Lutzke, L. S.

In: Journal of the National Cancer Institute, Vol. 94, No. 6, 20.03.2002, p. 422-429.

Research output: Contribution to journalArticle

Buttar, NS, Wang, KKN, Anderson, MA, Dierkhising, RA, Pacifico, RJ, Krishnadath, KK & Lutzke, LS 2002, 'The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: An in vitro study', Journal of the National Cancer Institute, vol. 94, no. 6, pp. 422-429.
Buttar, Navtej Singh ; Wang, Kenneth Ke Ning ; Anderson, Marlys A. ; Dierkhising, Ross A. ; Pacifico, Rodney J. ; Krishnadath, Krishnawatie K. ; Lutzke, L. S. / The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium : An in vitro study. In: Journal of the National Cancer Institute. 2002 ; Vol. 94, No. 6. pp. 422-429.
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abstract = "Background: Individuals with Barrett's esophagus, in which the normal squamous esophageal epithelium is replaced with a columnar mucosa, are at increased risk for esophageal adenocarcinoma. Mucosal injury may be involved in the progression to neoplasia via the synthesis of prostaglandins and other mediators of inflammation. Cyclooxygenase (COX)-2 is the rate-limiting enzyme involved in prostaglandin synthesis. We examined the effect of inhibiting COX-2 activity in Barrett's esophageal cells. Methods: Primary esophageal epithelial and fibroblast cell cultures were established from endoscopic biopsy specimens from 20 consecutive patients with Barrett's esophagus. COX-2 expression and activity were determined on pooled cell cultures by reverse transcription-polymerase chain reaction and prostaglandin E2 (PGE2) enzyme immunoassay, respectively. Proliferation was measured by Ki-67 staining. PGE2 levels were determined in supernatants from epithelial cells treated with the selective COX-2 inhibitor NS-398, proinflammatory cytokines (interleukin 1β and tumor necrosis factor-α), and conditioned medium from fibroblast cultures (both unstimulated and stimulated with proinflammatory cytokines). Results: Esophageal epithelial cells and fibroblasts expressed COX-2 messenger RNA. Compared with control-treated cells, NS-398 decreased proliferation of Barrett's esophageal epithelial cells by 55{\%} (95{\%} confidence interval = 47.1{\%} to 63.8{\%}; P<.001) and decreased COX-2 activity. The addition of exogenous PGE2 reversed the antiproliferative effect of NS-398 on Barrett's esophageal epithelial cells. Proinflammatory cytokines did not affect COX-2 activity in esophageal epithelial cells but stimulated COX-2 activity in fibroblasts. However, conditioned medium from unstimulated and stimulated fibroblasts increased COX-2 activity in esophageal epithelial cells. Conclusion: COX-2 is functionally active in Barrett's esophagus because treatment with the COX-2 inhibitor hinders proliferation of Barrett's esophageal epithelial cells in culture, but proliferation is restored by treatment with prostaglandin. These results raise the possibility that inhibition of COX-2 may have chemopreventive potential for Barrett's esophagus.",
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AU - Buttar, Navtej Singh

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AU - Dierkhising, Ross A.

AU - Pacifico, Rodney J.

AU - Krishnadath, Krishnawatie K.

AU - Lutzke, L. S.

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