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. 2001 May;84(10):1412–1416. doi: 10.1054/bjoc.2001.1807

Chemoprevention of intestinal tumorigenesis by nabumetone: induction of apoptosis and Bcl-2 downregulation

H K Roy 1, W J Karoski 1, A Ratashak 1, T C Smyrk 2
PMCID: PMC2363636  PMID: 11355956

Abstract

Treatment of MIN mice with the nonsteroidal anti-inflammatory drug, nabumetone, resulted in a dose-dependent suppression of intestinal tumorigenesis. In both the uninvolved MIN mouse colonic epithelium and HT-29 colon cancer cells, nabumetone downregulated the anti-apoptotic protein, Bcl-2, with concomitant induction of apoptosis, suggesting a potential mechanism for colon cancer chemoprevention. © 2001 Cancer Research Campaign www.bjcancer.com

Keywords: colon cancer, nonsteroidal anti-inflammatory drugs, apoptosis

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Selected References

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  1. Baretton G. B., Diebold J., Christoforis G., Vogt M., Müller C., Dopfer K., Schneiderbanger K., Schmidt M., Löhrs U. Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Aspects of carcinogenesis and prognostic significance. Cancer. 1996 Jan 15;77(2):255–264. doi: 10.1002/(SICI)1097-0142(19960115)77:2<255::AID-CNCR6>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  2. Barnes C. J., Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology. 1998 May;114(5):873–877. doi: 10.1016/s0016-5085(98)70305-1. [DOI] [PubMed] [Google Scholar]
  3. Beazer-Barclay Y., Levy D. B., Moser A. R., Dove W. F., Hamilton S. R., Vogelstein B., Kinzler K. W. Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis. 1996 Aug;17(8):1757–1760. doi: 10.1093/carcin/17.8.1757. [DOI] [PubMed] [Google Scholar]
  4. Bombardier C., Laine L., Reicin A., Shapiro D., Burgos-Vargas R., Davis B., Day R., Ferraz M. B., Hawkey C. J., Hochberg M. C. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528. doi: 10.1056/NEJM200011233432103. [DOI] [PubMed] [Google Scholar]
  5. Boolbol S. K., Dannenberg A. J., Chadburn A., Martucci C., Guo X. J., Ramonetti J. T., Abreu-Goris M., Newmark H. L., Lipkin M. L., DeCosse J. J. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996 Jun 1;56(11):2556–2560. [PubMed] [Google Scholar]
  6. Carr N. J. M30 expression demonstrates apoptotic cells, correlates with in situ end-labeling, and is associated with Ki-67 expression in large intestinal neoplasms. Arch Pathol Lab Med. 2000 Dec;124(12):1768–1772. doi: 10.5858/2000-124-1768-MEDACC. [DOI] [PubMed] [Google Scholar]
  7. Chulada P. C., Thompson M. B., Mahler J. F., Doyle C. M., Gaul B. W., Lee C., Tiano H. F., Morham S. G., Smithies O., Langenbach R. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res. 2000 Sep 1;60(17):4705–4708. [PubMed] [Google Scholar]
  8. Chung D. C. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000 Sep;119(3):854–865. doi: 10.1053/gast.2000.16507. [DOI] [PubMed] [Google Scholar]
  9. Hague A., Bracey T. S., Hicks D. J., Reed J. C., Paraskeva C. Decreased levels of p26-Bcl-2, but not p30 phosphorylated Bcl-2, precede TGFbeta1-induced apoptosis in colorectal adenoma cells. Carcinogenesis. 1998 Sep;19(9):1691–1695. doi: 10.1093/carcin/19.9.1691. [DOI] [PubMed] [Google Scholar]
  10. Huang J. Q., Sridhar S., Hunt R. H. Gastrointestinal safety profile of nabumetone: a meta-analysis. Am J Med. 1999 Dec 13;107(6A):55S–64S. doi: 10.1016/s0002-9343(99)00368-x. [DOI] [PubMed] [Google Scholar]
  11. Jänne P. A., Mayer R. J. Chemoprevention of colorectal cancer. N Engl J Med. 2000 Jun 29;342(26):1960–1968. doi: 10.1056/NEJM200006293422606. [DOI] [PubMed] [Google Scholar]
  12. Liu L. U., Holt P. R., Krivosheyev V., Moss S. F. Human right and left colon differ in epithelial cell apoptosis and in expression of Bak, a pro-apoptotic Bcl-2 homologue. Gut. 1999 Jul;45(1):45–50. doi: 10.1136/gut.45.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McAdam B. F., Catella-Lawson F., Mardini I. A., Kapoor S., Lawson J. A., FitzGerald G. A. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):272–277. doi: 10.1073/pnas.96.1.272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McEntee M. F., Chiu C. H., Whelan J. Relationship of beta-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice. Carcinogenesis. 1999 Apr;20(4):635–640. doi: 10.1093/carcin/20.4.635. [DOI] [PubMed] [Google Scholar]
  15. Roy H. K., Bissonnette M., Frawley B. P., Jr, Wali R. K., Niedziela S. M., Earnest D., Brasitus T. A. Selective preservation of protein kinase C-zeta in the chemoprevention of azoxymethane-induced colonic tumors by piroxicam. FEBS Lett. 1995 Jun 12;366(2-3):143–145. doi: 10.1016/0014-5793(95)00515-b. [DOI] [PubMed] [Google Scholar]
  16. Sheng H., Shao J., Morrow J. D., Beauchamp R. D., DuBois R. N. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998 Jan 15;58(2):362–366. [PubMed] [Google Scholar]
  17. Torrance C. J., Jackson P. E., Montgomery E., Kinzler K. W., Vogelstein B., Wissner A., Nunes M., Frost P., Discafani C. M. Combinatorial chemoprevention of intestinal neoplasia. Nat Med. 2000 Sep;6(9):1024–1028. doi: 10.1038/79534. [DOI] [PubMed] [Google Scholar]
  18. Tsujimoto Y., Shimizu S. Bcl-2 family: life-or-death switch. FEBS Lett. 2000 Jan 21;466(1):6–10. doi: 10.1016/s0014-5793(99)01761-5. [DOI] [PubMed] [Google Scholar]
  19. Warner T. D., Giuliano F., Vojnovic I., Bukasa A., Mitchell J. A., Vane J. R. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7563–7568. doi: 10.1073/pnas.96.13.7563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Williams C. S., Smalley W., DuBois R. N. Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest. 1997 Sep 15;100(6):1325–1329. doi: 10.1172/JCI119651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Winde G., Schmid K. W., Brandt B., Müller O., Osswald H. Clinical and genomic influence of sulindac on rectal mucosa in familial adenomatous polyposis. Dis Colon Rectum. 1997 Oct;40(10):1156–1169. doi: 10.1007/BF02055161. [DOI] [PubMed] [Google Scholar]
  22. Zhang L., Yu J., Park B. H., Kinzler K. W., Vogelstein B. Role of BAX in the apoptotic response to anticancer agents. Science. 2000 Nov 3;290(5493):989–992. doi: 10.1126/science.290.5493.989. [DOI] [PubMed] [Google Scholar]

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