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J Clin Invest. Jul 1995; 96(1): 491–503.
PMCID: PMC185223

Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells.

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs), have cancer preventive and tumor regressive effects in the human colon. They lower the incidence of and mortality from colorectal cancer and sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We studied the effect of sulindac, and its metabolite sulindac sulfide, on the proliferation of HT-29 colon adenocarcinoma cells. Both compounds reduced the proliferation rate of these cells, changed their morphology, and caused them to accumulate in the G0/G1 phase of the cell cycle. These responses were time- and concentration-dependent and reversible. In addition, these compounds reduced the level and activity of several cyclin-dependent kinases (cdks), which regulate cell cycle progression. Sulindac and sulindac sulfide also induced apoptosis in these cells at concentrations that affected their proliferation, morphology, and cell cycle phase distribution. Sulindac sulfide was approximately sixfold more potent than sulindac in inducing these cellular responses. Our results indicate that inhibition of cell cycle progression and induction of apoptotic cell death contribute to the anti-proliferative effects of sulindac and sulindac sulfide in HT-29 cells. These findings may be relevant to the cancer preventive and tumor regressive effects of these compounds in humans.

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These references are in PubMed. This may not be the complete list of references from this article.
  • Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG, Hoover R, Fraumeni JF., Jr Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst. 1993 Feb 17;85(4):307–311. [PubMed]
  • Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med. 1994 Aug 15;121(4):241–246. [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]
  • Thorson AG, Lynch HT, Smyrk TC. Rectal cancer in FAP patient after sulindac. Lancet. 1994 Jan 15;343(8890):180–180. [PubMed]
  • Reddy BS, Rao CV, Rivenson A, Kelloff G. Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis. 1993 Aug;14(8):1493–1497. [PubMed]
  • Moorghen M, Ince P, Finney KJ, Sunter JP, Appleton DR, Watson AJ. A protective effect of sulindac against chemically-induced primary colonic tumours in mice. J Pathol. 1988 Dec;156(4):341–347. [PubMed]
  • Pollard M, Luckert PH, Schmidt MA. The suppressive effect of piroxicam on autochthonous intestinal tumors in the rat. Cancer Lett. 1983 Nov;21(1):57–61. [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]
  • Bayer BM, Kruth HS, Vaughan M, Beaven MA. Arrest of cultured cells in the G1 phase of the cell cycle by indomethacin. J Pharmacol Exp Ther. 1979 Jul;210(1):106–111. [PubMed]
  • Bayer BM, Beaven MA. Evidence that indomethacin reversibly inhibits cell growth in the G1 phase of the cell cycle. Biochem Pharmacol. 1979;28(3):441–443. [PubMed]
  • Sherr CJ. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. [PubMed]
  • Pines J. Arresting developments in cell-cycle control. Trends Biochem Sci. 1994 Apr;19(4):143–145. [PubMed]
  • Fang F, Newport JW. Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell. 1991 Aug 23;66(4):731–742. [PubMed]
  • Riabowol K, Draetta G, Brizuela L, Vandre D, Beach D. The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells. Cell. 1989 May 5;57(3):393–401. [PubMed]
  • van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050–2054. [PubMed]
  • Pines J, Hunter T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell. 1989 Sep 8;58(5):833–846. [PubMed]
  • Tsai LH, Lees E, Faha B, Harlow E, Riabowol K. The cdk2 kinase is required for the G1-to-S transition in mammalian cells. Oncogene. 1993 Jun;8(6):1593–1602. [PubMed]
  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992 Sep 18;257(5077):1689–1694. [PubMed]
  • Dulić V, Lees E, Reed SI. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. [PubMed]
  • Ohtsubo M, Roberts JM. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993 Mar 26;259(5103):1908–1912. [PubMed]
  • Resnitzky D, Gossen M, Bujard H, Reed SI. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol. 1994 Mar;14(3):1669–1679. [PMC free article] [PubMed]
  • Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell. 1992 Oct 16;71(2):323–334. [PubMed]
  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994 Mar;14(3):2066–2076. [PMC free article] [PubMed]
  • Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077–2086. [PMC free article] [PubMed]
  • Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. [PubMed]
  • Draetta G, Beach D. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell. 1988 Jul 1;54(1):17–26. [PubMed]
  • Rosenblatt J, Gu Y, Morgan DO. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2824–2828. [PMC free article] [PubMed]
  • Adolphe M, Deysson G, Lechat P. Action of some steroid and non-steroid anti-inflammatory agents on the cell cycle: cytophotometric study of the DNA content. Rev Eur Etud Clin Biol. 1972 Mar;17(3):320–323. [PubMed]
  • Strong HA, Warner NJ, Renwick AG, George CF. Sulindac metabolism: the importance of an intact colon. Clin Pharmacol Ther. 1985 Oct;38(4):387–393. [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]
  • Duggan DE, Hooke KF, Hwang SS. Kinetics of the tissue distributions of sulindac and metabolites. Relevance to sites and rates of bioactivation. Drug Metab Dispos. 1980 Jul-Aug;8(4):241–246. [PubMed]
  • Swanson BN, Boppana VK, Vlasses PH, Holmes GI, Monsell K, Ferguson RK. Sulindac disposition when given once and twice daily. Clin Pharmacol Ther. 1982 Sep;32(3):397–403. [PubMed]
  • Duggan DE, Hare LE, Ditzler CA, Lei BW, Kwan KC. The disposition of sulindac. Clin Pharmacol Ther. 1977 Mar;21(3):326–335. [PubMed]
  • Cohen JJ. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. [PubMed]
  • Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994 Apr 15;73(8):2013–2026. [PubMed]
  • Vaux DL, Haecker G, Strasser A. An evolutionary perspective on apoptosis. Cell. 1994 Mar 11;76(5):777–779. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. [PubMed]
  • Elstein KH, Zucker RM. Comparison of cellular and nuclear flow cytometric techniques for discriminating apoptotic subpopulations. Exp Cell Res. 1994 Apr;211(2):322–331. [PubMed]
  • Darzynkiewicz Z, Bruno S, Del Bino G, Gorczyca W, Hotz MA, Lassota P, Traganos F. Features of apoptotic cells measured by flow cytometry. Cytometry. 1992;13(8):795–808. [PubMed]
  • Darzynkiewicz Z. Differential staining of DNA and RNA in intact cells and isolated cell nuclei with acridine orange. Methods Cell Biol. 1990;33:285–298. [PubMed]
  • Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. [PubMed]
  • Tsai LH, Harlow E, Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature. 1991 Sep 12;353(6340):174–177. [PubMed]
  • Neupert G, Müller P. Growth inhibition and morphological changes caused by indomethacin in fibroblasts in vitro. Exp Pathol (Jena) 1975;11(1-2):1–9. [PubMed]
  • Karzel K, Aulepp H, Hack G. Effects of recently developed antiphlogistic drugs on viability, reduplication, mean volume and volume distribution of mammalian cells cultured in vitro. Pharmacology. 1973;10(5):272–290. [PubMed]
  • Hial V, De Mello MC, Horakova Z, Beaven MA. Antiproliferative activity of anti-inflammatory drugs in two mammalian cell culture lines. J Pharmacol Exp Ther. 1977 Aug;202(2):446–454. [PubMed]
  • Kirkpatrick CJ, Mohr W, Mildfeuer A, Haferkamp O. Influence of nonsteroidal anti-inflammatory agents on lapine articular chondrocyte growth in vitro. Z Rheumatol. 1983 Mar-Apr;42(2):58–65. [PubMed]
  • Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993 Mar 25;268(9):6610–6614. [PubMed]
  • Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. [PubMed]
  • Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993 Sep 24;74(6):957–967. [PubMed]
  • Wolf D, Rotter V. Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc Natl Acad Sci U S A. 1985 Feb;82(3):790–794. [PMC free article] [PubMed]
  • Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF, Gannon JV, Lane DP. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7555–7559. [PMC free article] [PubMed]
  • Lee FD. Importance of apoptosis in the histopathology of drug related lesions in the large intestine. J Clin Pathol. 1993 Feb;46(2):118–122. [PMC free article] [PubMed]
  • Potten CS, Li YQ, O'Connor PJ, Winton DJ. A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel. Carcinogenesis. 1992 Dec;13(12):2305–2312. [PubMed]
  • Cummings JH. Short chain fatty acids in the human colon. Gut. 1981 Sep;22(9):763–779. [PMC free article] [PubMed]
  • Hague A, Manning AM, Hanlon KA, Huschtscha LI, Hart D, Paraskeva C. Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer. Int J Cancer. 1993 Sep 30;55(3):498–505. [PubMed]

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