title: Sulindac inhibits beta-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients.
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-beta-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, beta-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, beta-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 beta-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 beta-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands.
authors: Jan J
authors: JJ
authors: Koornstra
authors: Fleur E M
authors: FE
authors: Rijcken
authors: Corina N A M
authors: CN
authors: Oldenhuis
authors: Nynke
authors: N
authors: Zwart
authors: Tineke
authors: T
authors: van der Sluis
authors: Harry
authors: H
authors: Hollema
authors: Elisabeth G E
authors: EG
authors: deVries
authors: Josbert J
authors: JJ
authors: Keller
authors: Johan A
authors: JA
authors: Offerhaus
authors: Francis M
authors: FM
authors: Giardiello
authors: Jan H
authors: JH
authors: Kleibeuker
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D013467:Sulindac / Q000627:therapeutic use*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D051176:beta Catenin
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D013467:Sulindac