Sulindac Inhibits β-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 14; no. 7; pp. 1608 - 1612
• Main Authors: KOORNSTRA, Jan J, RIJCKEN, Fleur E. M, KLEIBEUKER, Jan H, 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
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-2005
• Subjects: Adenomatous Polyposis Coli - drug therapy; Adenomatous Polyposis Coli - genetics; Adult; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antineoplastic agents; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - drug effects; beta Catenin; Biological and medical sciences; Biomarkers, Tumor; Chemotherapy; Colorectal Neoplasms - prevention & control; Cytoskeletal Proteins - antagonists & inhibitors; FAP; Female; HNPCC; Humans; Male; Medical sciences; Pharmacology. Drug treatments; sulindac; Sulindac - therapeutic use; TRAIL; Trans-Activators - antagonists & inhibitors; Tumors; Antineoplastic agent; Prostaglandin-endoperoxide synthase; Chemoprophylaxis; Rectal disease; Colorectal cancer; CDKN1A Gene; Prevention; Death receptor 5; Death receptor 4; Cancerology; Sulindac; Genetics; Intestinal disease; Indene derivatives; Benign neoplasm; Public health; Tumor suppressor gene; Human; Enzyme; Enzyme inhibitor; Malignant tumor; Familial adenomatous polyposis coli; Acetic acid derivative; Hereditary; Genetic disease; Colonic disease; Non steroidal antiinflammatory agent; Cell death; β Catenin; Digestive diseases; Oxidoreductases; Apoptosis
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.EPI-05-0112

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.