Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients

Jan J. Koornstra, Fleur E M Rijcken, Corina N A M Oldenhuis, Nynke Zwart, Tineke Van Der Sluis, Harry Hollema, Elisabeth G E DeVries, Josbert J. Keller, Johan A. Offerhaus, Francis M Giardiello, Jan H. Kleibeuker

Research output: Contribution to journalArticle

Abstract

Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-β-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, β-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, β-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/ baseline and sulindac. Intensity of membranous β-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P <0.001). Similar results were obtained in FAP samples (P <0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits β-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.

Original languageEnglish (US)
Pages (from-to)1608-1612
Number of pages5
JournalCancer Epidemiology Biomarkers and Prevention
Volume14
Issue number7
DOIs
StatePublished - Jul 2005

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Sulindac
Hereditary Nonpolyposis Colorectal Neoplasms
Catenins
Adenomatous Polyposis Coli
Colon
Placebos
Apoptosis
Epithelium
TNF-Related Apoptosis-Inducing Ligand Receptors
Staining and Labeling
Death Domain Receptors
Wnt Signaling Pathway
Chemoprevention
Cross-Over Studies
Colorectal Neoplasms

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients. / Koornstra, Jan J.; Rijcken, Fleur E M; Oldenhuis, Corina N A M; Zwart, Nynke; Van Der Sluis, Tineke; Hollema, Harry; DeVries, Elisabeth G E; Keller, Josbert J.; Offerhaus, Johan A.; Giardiello, Francis M; Kleibeuker, Jan H.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 14, No. 7, 07.2005, p. 1608-1612.

Research output: Contribution to journalArticle

Koornstra, JJ, Rijcken, FEM, Oldenhuis, CNAM, Zwart, N, Van Der Sluis, T, Hollema, H, DeVries, EGE, Keller, JJ, Offerhaus, JA, Giardiello, FM & Kleibeuker, JH 2005, 'Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients', Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 7, pp. 1608-1612. https://doi.org/10.1158/1055-9965.EPI-05-0112
Koornstra, Jan J. ; Rijcken, Fleur E M ; Oldenhuis, Corina N A M ; Zwart, Nynke ; Van Der Sluis, Tineke ; Hollema, Harry ; DeVries, Elisabeth G E ; Keller, Josbert J. ; Offerhaus, Johan A. ; Giardiello, Francis M ; Kleibeuker, Jan H. / Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients. In: Cancer Epidemiology Biomarkers and Prevention. 2005 ; Vol. 14, No. 7. pp. 1608-1612.
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abstract = "Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-β-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, β-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, β-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/ baseline and sulindac. Intensity of membranous β-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P <0.001). Similar results were obtained in FAP samples (P <0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits β-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.",
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AU - Rijcken, Fleur E M

AU - Oldenhuis, Corina N A M

AU - Zwart, Nynke

AU - Van Der Sluis, Tineke

AU - Hollema, Harry

AU - DeVries, Elisabeth G E

AU - Keller, Josbert J.

AU - Offerhaus, Johan A.

AU - Giardiello, Francis M

AU - Kleibeuker, Jan H.

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