PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of gutGutView this articleSubmit a manuscriptReceive email alertsContact usBMJ
 
Gut. 1996 May; 38(5): 707–713.
PMCID: PMC1383152

Sulindac increases the expression of APC mRNA in malignant colonic epithelial cells: an in vitro study.

Abstract

BACKGROUND--Sulindac is a non-steroidal anti-inflammatory drug which induces regression of colonic polyps in patients with familial adenomatous polyposis. Animal and in vitro studies have shown that both the sulphide metabolite of sulindac, which is able to inhibit cyclo-oxygenase, and the sulphone metabolite, which lacks this ability, are able to inhibit the growth of colonic carcinoma cells. The exact mechanism by which these effects occurs is not known. AIMS--To examine the effect of sulindac sulphide and sulindac sulphone on the expression of APC messenger RNA (mRNA), and on the proliferation of colonic carcinoma cells in vitro. METHODS--The colonic carcinoma cell line LIM 1215 was treated with sulindac sulphide and sulindac sulphone (10 microM or 100 microM) for 24 hours. Total RNA was extracted and APC mRNA was quantitated using competitive reverse transcription polymerase chain reaction. Measurements of cell number, cell proliferation, and prostaglandin E2 concentrations were also made. RESULTS--A significant increase in APC mRNA was observed after treatment with 10 microM of both sulindac sulphide and sulindac sulphone (control: 37.2 (19.7); 10 microM sulindac sulphide: 129 (112.8); 10 microM sulindac sulphone: 207.7 (102.9) pg/(g total RNA) (p < 0.05). Prostaglandin E2 concentrations were significantly reduced after treatment with sulindac sulphide, but not after sulindac sulphone. Both agents produced a dose dependent reduction in cell numbers and cell proliferation, which was more noticeable after treatment with sulindac sulphide. CONCLUSIONS--Both sulindac sulphide and sulindac sulphone inhibit the growth of carcinoma cells in vitro and cause an increase in APC mRNA. The effect of these agents on colonic carcinogenesis is not mediated entirely by means of an inhibition of prostaglandin biosynthesis.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Duggan DE, Hooke KF, Risley EA, Shen TY, Arman CG. Identification of the biologically active form of sulindac. J Pharmacol Exp Ther. 1977 Apr;201(1):8–13. [PubMed]
  • Waddell WR, Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol. 1983 Sep;24(1):83–87. [PubMed]
  • Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313–1316. [PubMed]
  • Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology. 1991 Sep;101(3):635–639. [PubMed]
  • Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 1993 Dec;80(12):1618–1619. [PubMed]
  • Rigau J, Piqué JM, Rubio E, Planas R, Tarrech JM, Bordas JM. Effects of long-term sulindac therapy on colonic polyposis. Ann Intern Med. 1991 Dec 15;115(12):952–954. [PubMed]
  • Hucker HB, Stauffer SC, White SD, Rhodes RE, Arison BH, Umbenhauer ER, Bower RJ, McMahon FG. Physiologic disposition and metabolic fate of a new anti-inflammatory agent, cis-5-fluro-2-methyl-1-(p-(methylsulfinyl)-benzylidenyl)-indene-3-acetic acid in the rat, dog, rhesus monkey, and man. Drug Metab Dispos. 1973 Nov-Dec;1(6):721–736. [PubMed]
  • Niv Y, Fraser GM. Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. Gastroenterology. 1994 Sep;107(3):854–857. [PubMed]
  • Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged sulindac chemoprevention. A case report. Cancer. 1995 Feb 15;75(4):936–938. [PubMed]
  • Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg. 1989 Jan;157(1):175–179. [PubMed]
  • Hixson LJ, Earnest DL, Fennerty MB, Sampliner RE. NSAID effect on sporadic colon polyps. Am J Gastroenterol. 1993 Oct;88(10):1652–1656. [PubMed]
  • Ladenheim J, Garcia G, Titzer D, Herzenberg H, Lavori P, Edson R, Omary MB. Effect of sulindac on sporadic colonic polyps. Gastroenterology. 1995 Apr;108(4):1083–1087. [PubMed]
  • Craven PA, DeRubertis FR. Effects of aspirin on 1,2-dimethylhydrazine-induced colonic carcinogenesis. Carcinogenesis. 1992 Apr;13(4):541–546. [PubMed]
  • Craven PA, Thornburg K, DeRubertis FR. Sustained increase in the proliferation of rat colonic mucosa during chronic treatment with aspirin. Gastroenterology. 1988 Mar;94(3):567–575. [PubMed]
  • Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992 Jul;1(4):229–233. [PubMed]
  • Nagase H, Nakamura Y. Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat. 1993;2(6):425–434. [PubMed]
  • Rubinfeld B, Souza B, Albert I, Müller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. [PubMed]
  • Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. [PubMed]
  • Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3046–3050. [PubMed]
  • Munemitsu S, Souza B, Müller O, Albert I, Rubinfeld B, Polakis P. The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res. 1994 Jul 15;54(14):3676–3681. [PubMed]
  • Smith KJ, Levy DB, Maupin P, Pollard TD, Vogelstein B, Kinzler KW. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 1994 Jul 15;54(14):3672–3675. [PubMed]
  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. [PubMed]
  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. [PubMed]
  • Whitehead RH, Macrae FA, St John DJ, Ma J. A colon cancer cell line (LIM1215) derived from a patient with inherited nonpolyposis colorectal cancer. J Natl Cancer Inst. 1985 Apr;74(4):759–765. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Debinski HS, Trojan J, Nugent KP, Spigelman AD, Phillips RK. Effect of sulindac on small polyps in familial adenomatous polyposis. Lancet. 1995 Apr 1;345(8953):855–856. [PubMed]
  • Pollard M, Luckert PH. Effect of indomethacin on intestinal tumors induced in rats by the acetate derivative of dimethylnitrosamine. Science. 1981 Oct 30;214(4520):558–559. [PubMed]
  • Narisawa T, Hermanek P, Habs M, Schmähl D. Reduction of carcinogenicity of N-nitrosomethylurea by indomethacin and failure of resuming effect of prostaglandin E2 (PGE2) against indomethacin. J Cancer Res Clin Oncol. 1984;108(2):239–242. [PubMed]
  • Hixson LJ, Alberts DS, Krutzsch M, Einsphar J, Brendel K, Gross PH, Paranka NS, Baier M, Emerson S, Pamukcu R, et al. Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. Cancer Epidemiol Biomarkers Prev. 1994 Jul-Aug;3(5):433–438. [PubMed]
  • Bennett A, Tacca MD, Stamford IF, Zebro T. Prostaglandins from tumours of human large bowel. Br J Cancer. 1977 Jun;35(6):881–884. [PubMed]
  • Knapp HR, Oelz O, Sweetman BJ, Oates JA. Synthesis and metabolism of prostaglandins E2, F2alpha and D2 by the rat gastrointestinal tract. Stimulation by a hypertonic environment in vitro. Prostaglandins. 1978 May;15(5):751–757. [PubMed]
  • Pugh S, Thomas GA. Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut. 1994 May;35(5):675–678. [PMC free article] [PubMed]
  • Hubbard WC, Alley MC, McLemore TL, Boyd MR. Profiles of prostaglandin biosynthesis in sixteen established cell lines derived from human lung, colon, prostate, and ovarian tumors. Cancer Res. 1988 Sep 1;48(17):4770–4775. [PubMed]
  • DuBois RN, Awad J, Morrow J, Roberts LJ, 2nd, Bishop PR. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest. 1994 Feb;93(2):493–498. [PMC free article] [PubMed]
  • Verma AK, Ashendel CL, Boutwell RK. Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 1980 Feb;40(2):308–315. [PubMed]
  • Bodmer WF, Bailey CJ, Bodmer J, Bussey HJ, Ellis A, Gorman P, Lucibello FC, Murday VA, Rider SH, Scambler P, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. [PubMed]
  • Su LK, Johnson KA, Smith KJ, Hill DE, Vogelstein B, Kinzler KW. Association between wild type and mutant APC gene products. Cancer Res. 1993 Jun 15;53(12):2728–2731. [PubMed]
  • Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JK, Paraskeva C, Petersen GM, Hamilton SR, Vogelstein B, et al. The APC gene product in normal and tumor cells. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2846–2850. [PubMed]
  • Lim SK, Sigmund CD, Gross KW, Maquat LE. Nonsense codons in human beta-globin mRNA result in the production of mRNA degradation products. Mol Cell Biol. 1992 Mar;12(3):1149–1161. [PMC free article] [PubMed]

Articles from Gut are provided here courtesy of BMJ Publishing Group