Current Colorectal Cancer Reports

, Volume 8, Issue 4, pp 325–330 | Cite as

Novel Therapeutics: NSAIDs, Derivatives, and Phosphodiesterases

Molecular Biology (S Anant, Section Editor)

Abstract

The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for colorectal cancer has been well documented. However, long-term use of NSAIDs is precluded owing to potentially fatal toxicities associated with their mechanism of action involving cyclooxygenase (COX) inhibition. But studies have shown that their anticancer activity may be due, in part, to an off-target effect. Cyclic guanosine monophosphate (cGMP) phosphodiesterases (PDEs), which are responsible for negative regulation of cGMP signaling, are an attractive COX-independent target. cGMP signaling is aberrantly suppressed in cancer cells and its activation appears to be sufficient to inhibit tumor cell growth. Chemically modifying sulindac has produced a series of new derivatives that lack COX-inhibitory activity but have improved cGMP PDE inhibitory activity. This approach is proving to be a promising strategy for the discovery of improved agents for the prevention and/or treatment of colorectal cancer.

Keywords

Sulindac Colon cancer Nonsteroidal anti-inflammatory drug Cyclic guanosine monophosphate Phosphodiesterase 

References

Papers of particular interest, published recently, have been highlighted as follows: • Of importance •• Of major importance

  1. 1.
    Earnest DL, Hixson LJ, Alberts DS. Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention. J Cell Biochem Suppl. 1992;16I:156–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Fischer SM, Hawk ET, Lubet RA. Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention. Cancer Prev Res (Phila). 2011;4(11):1728–35.CrossRefGoogle Scholar
  3. 3.
    Rao CV, Reddy BS. NSAIDs and chemoprevention. Curr Cancer Drug Targets. 2004;4(1):29–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Turner D, Berkel HJ. Nonsteroidal anti-inflammatory drugs for the prevention of colon cancer. CMAJ. 1993;149(5):595–602.PubMedGoogle Scholar
  5. 5.
    Bastiaannet E, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer. 2012;106(9):1564–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Bertagnolli MM, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355(9):873–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol. 2002;3(3):166–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Giardiello FM, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328(18):1313–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Matsuhashi N, et al. Effects of sulindac on sporadic colorectal adenomatous polyps. Gut. 1997;40(3):344–9.PubMedGoogle Scholar
  10. 10.
    Matsuhashi N, et al. Rectal cancer after sulindac therapy for a sporadic adenomatous colonic polyp. Am J Gastroenterol. 1998;93(11):2261–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Nugent KP, et al. 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;80(12):1618–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Phillips RK, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002;50(6):857–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Steinbach G, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342(26):1946–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst. 2002;94(4):252–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Thun MJ, Namboodiri MM, Heath Jr CW. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325(23):1593–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Williams CS, et al. Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res. 2000;60(21):6045–51.PubMedGoogle Scholar
  17. 17.
    Ruder EH, et al. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol. 2011;106(7):1340–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Elder DJ, et al. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res. 1997;3(10):1679–83.PubMedGoogle Scholar
  19. 19.
    Grosch S, et al. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. Faseb J. 2001;15(14):2742–4.PubMedGoogle Scholar
  20. 20.
    Hanif R, et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol. 1996;52(2):237–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Kusuhara H, et al. Induction of apoptotic DNA fragmentation by nonsteroidal anti-inflammatory drugs in cultured rat gastric mucosal cells. Eur J Pharmacol. 1998;360(2–3):273–80.PubMedCrossRefGoogle Scholar
  22. 22.
    Piazza GA, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res. 1995;55(14):3110–6.PubMedGoogle Scholar
  23. 23.
    •• Tinsley HN, et al. Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res (Phila), 2010;3(10):1303–13. This article demonstrates the link between the anticancer activity of NSAIDs, including sulindac, and cGMP PDE inhibition. CrossRefGoogle Scholar
  24. 24.
    Vane JR, Botting RM. Mechanism of action of antiinflammatory drugs. Int J Tissue React. 1998;20(1):3–15.PubMedGoogle Scholar
  25. 25.
    Alberts DS, et al. Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? J Cell Biochem Suppl. 1995;22:18–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97–120.PubMedCrossRefGoogle Scholar
  27. 27.
    Kashfi K, Rigas B. Is COX-2 a ‘collateral’ target in cancer prevention? Biochem Soc Trans. 2005;33(Pt 4):724–7.PubMedGoogle Scholar
  28. 28.
    Piazza GA, et al. Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res. 1997;57(14):2909–15.PubMedGoogle Scholar
  29. 29.
    • Piazza GA, et al. A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity. Cancer Prev Res (Phila Pa), 2009;2(6):572–80. This article presents the new approach to COX-independent NSAID design. CrossRefGoogle Scholar
  30. 30.
    • Piazza GA, et al. NSAIDs: Old drugs reveal new anticancer targets. Pharmaceuticals, 2010;3(5):1652–1667. This review discusses the proposed anticancer mechanisms of NSAIDs. CrossRefGoogle Scholar
  31. 31.
    Piazza GA, et al. Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res. 1997;57(12):2452–9.PubMedGoogle Scholar
  32. 32.
    Soh JW, et al. Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G. Mol Carcinog. 2008;47(7):519–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Thompson WJ, et al. Exisulind induction of apoptosis involves guanosine 3′,5′-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000;60(13):3338–42.PubMedGoogle Scholar
  34. 34.
    Schmidt H. Cgmp: generators, effectors and therapeutic implications. New York, NY: Springer Heidelberg; 2008.Google Scholar
  35. 35.
    Feil R, Kemp-Harper B. cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications. EMBO Rep. 2006;7(2):149–53.PubMedCrossRefGoogle Scholar
  36. 36.
    Lincoln TM, Cornwell TL. Intracellular cyclic GMP receptor proteins. FASEB J. 1993;7(2):328–38.PubMedGoogle Scholar
  37. 37.
    Beavo J, Francis SH, and Houslay MD. Cyclic nucleotide phosphodiesterases in health and disease. Boca Raton: CRC; 2007. 713 p. 38 p. of plates.Google Scholar
  38. 38.
    Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995;75(4):725–48.PubMedGoogle Scholar
  39. 39.
    Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58(3):488–520.PubMedCrossRefGoogle Scholar
  40. 40.
    Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76:481–511.PubMedCrossRefGoogle Scholar
  41. 41.
    Sindic A, Schlatter E. Mechanisms of action of uroguanylin and guanylin and their role in salt handling. Nephrol Dial Transplant. 2006;21(11):3007–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Sindic A, Schlatter E. Cellular effects of guanylin and uroguanylin. J Am Soc Nephrol. 2006;17(3):607–16.PubMedCrossRefGoogle Scholar
  43. 43.
    Birbe R, et al. Guanylyl cyclase C is a marker of intestinal metaplasia, dysplasia, and adenocarcinoma of the gastrointestinal tract. Hum Pathol. 2005;36(2):170–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Browning DD, Kwon IK, Wang R. cGMP-dependent protein kinases as potential targets for colon cancer prevention and treatment. Future Med Chem. 2010;2(1):65–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Li P, Waldman SA. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis. Cancer Biol Ther. 2010;10(3):211–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Pitari GM, et al. Interruption of homologous desensitization in cyclic guanosine 3′,5′-monophosphate signaling restores colon cancer cytostasis by bacterial enterotoxins. Cancer Res. 2005;65(23):11129–35.PubMedCrossRefGoogle Scholar
  47. 47.
    Pitari GM, et al. Bacterial enterotoxins are associated with resistance to colon cancer. Proc Natl Acad Sci U S A. 2003;100(5):2695–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Camici M. Guanylin peptides and colorectal cancer (CRC). Biomed Pharmacother. 2008;62(2):70–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Steinbrecher KA, et al. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation. Am J Pathol. 2002;161(6):2169–78.PubMedCrossRefGoogle Scholar
  50. 50.
    Waldman SA, et al. Heterogeneity of guanylyl cyclase C expressed by human colorectal cancer cell lines in vitro. Cancer Epidemiol Biomarkers Prev. 1998;7(6):505–14.PubMedGoogle Scholar
  51. 51.
    Kwon IK, et al. Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis. Cancer. 2008;112(7):1462–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Deguchi A, Thompson WJ, Weinstein IB. Activation of protein kinase G is sufficient to induce apoptosis and inhibit cell migration in colon cancer cells. Cancer Res. 2004;64(11):3966–73.PubMedCrossRefGoogle Scholar
  53. 53.
    Pitari GM, et al. Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells. Proc Natl Acad Sci USA. 2001;98(14):7846–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Shailubhai K, et al. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP. Cancer Res. 2000;60(18):5151–7.PubMedGoogle Scholar
  55. 55.
    Soh JW, et al. Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res. 2000;6(10):4136–41.PubMedGoogle Scholar
  56. 56.
    Zhu B, et al. Suppression of cyclic GMP-specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29 cells. J Cell Biochem. 2005;94(2):336–50.PubMedCrossRefGoogle Scholar
  57. 57.
    Li P, et al. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007;133(2):599–607.PubMedCrossRefGoogle Scholar
  58. 58.
    Kwon IK, et al. PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene. 2010;29(23):3423–34.PubMedCrossRefGoogle Scholar
  59. 59.
    Tinsley HN, et al. Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells. Cancer Prev Res (Phila). 2011;4(8):1275–84.CrossRefGoogle Scholar
  60. 60.
    Tinsley HN, et al. Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G. Mol Cancer Ther. 2009;8(12):3331–40.PubMedCrossRefGoogle Scholar
  61. 61.
    •• Whitt JD, et al. A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and beta-catenin transcriptional activity. Cancer Prev Res (Phila), 2012;5(6):822–33. This article presents the new approach to COX-independent NSAID design. CrossRefGoogle Scholar
  62. 62.
    Eheman C, et al. Annual report to the nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. 2012;118(9):2338–66.PubMedCrossRefGoogle Scholar
  63. 63.
    Bischoff E. Potency, selectivity, and consequences of nonselectivity of PDE inhibition. Int J Impot Res. 2004;16 Suppl 1:S11–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Abadi AH, et al. Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective. Eur J Med Chem. 2010;45(4):1278–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Ahmed NS, et al. Design, synthesis and structure-activity relationship of functionalized tetrahydro-beta-carboline derivatives as novel PDE5 inhibitors. Arch Pharm (Weinheim). 2011;344(3):149–57.CrossRefGoogle Scholar
  66. 66.
    Mohamed HA, et al. Synthesis and molecular modeling of novel tetrahydro-beta-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties. J Med Chem. 2011;54(2):495–509.PubMedCrossRefGoogle Scholar
  67. 67.
    Ahmed NS, et al. A novel access to arylated and heteroarylated beta-carboline based PDE5 inhibitors. Med Chem. 2010;6(6):374–87.PubMedCrossRefGoogle Scholar
  68. 68.
    Abadi AH, et al. Discovery of colon tumor cell growth inhibitory agents through a combinatorial approach. Eur J Med Chem. 2010;45(1):90–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Abadi AH, et al. Synthesis of novel tadalafil analogues and their evaluation as phosphodiesterase inhibitors and anticancer agents. Arzneimittelforschung. 2009;59(8):415–21.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of BiologyChemistry and Mathematics, University of MontevalloMontevalloUSA
  2. 2.Drug Discovery Research CenterMitchell Cancer Institute, University of South AlabamaMobileUSA

Personalised recommendations