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Select Cyclic Nucleotide Phosphodiesterase Inhibitors in Colon Tumor Chemoprevention and Chemotherapy

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Cancer Chemoprevention

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Exisulind, and later generation drugs including CP461, are members of a group of new anticancer compounds known as Selective Apoptotic Antineoplastic Drugs (SAANDs). These drugs act by selectively inducing apoptosis in precancerous and cancerous tissues. Exisulind is a metabolite of sulindac, a nonsteroidal antiinflammatory drug (NSAID). Although initially developed to prevent colon cancer, exisulind and CP461 are currently being tested in clinical trials as chemotherapeutics against many types of cancer, including breast, colon, lung, prostate, chronic lymphocytic leukemia, and renal cell carcinoma. SAANDs were screened as cyclic 5′ guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibitors with a preference for the PDE5 gene family. Published data have shown that in a colon cancer model, these drugs increase cGMP levels, activate cGMP-dependent protein kinase G (PKG) to stimulate the Jun kinase (JNK) regulatory cascade, and cause a decrease in accumulated nuclear and cytosolic β-catenin followed by reduced cyclin D1 transcription.

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References

  1. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–1316.

    Article  PubMed  CAS  Google Scholar 

  2. Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg 1989;157:175–179.

    Article  PubMed  CAS  Google Scholar 

  3. Rigau J, Pique JM, Rubio E, et al. Effects of long-term sulindac therapy on colonic polyposis. Ann Intern Med 1991;115:952–954.

    PubMed  CAS  Google Scholar 

  4. Labayle D, Fischer D, Vielh P, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991;101:635–639.

    PubMed  CAS  Google Scholar 

  5. Dobrinska MR, Furst DE, Spiegel T, et al. Biliary secretion of sulindac and metabolites in man. Biopharm Drug Dispos 1983;4:347–358.

    Article  PubMed  CAS  Google Scholar 

  6. 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;8:241–246.

    PubMed  CAS  Google Scholar 

  7. Shen TY, Winter CA. Chemical and biological studies on indomethacin, sulindac and their analogs. Adv Drug Res 1977;12:90–245.

    PubMed  CAS  Google Scholar 

  8. Haanen C. Sulindac and its derivatives: a novel class of anticancer agents. Curr Opin Investig Drugs 2001;2:677–683.

    PubMed  CAS  Google Scholar 

  9. Salter EA, Wierzbicki A, Sperl G, Thompson WJ. Molecular modeling study of COX-2 inhibition by diarylheterocycles and sulindac sulfide. J Mol Struct 2001;549:111–121.

    Article  CAS  Google Scholar 

  10. Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol Suppl 1996;102:9–21.

    Article  PubMed  CAS  Google Scholar 

  11. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:2S–8S.

    Article  PubMed  CAS  Google Scholar 

  12. Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 1992;52:5575–5589.

    PubMed  CAS  Google Scholar 

  13. Thompson HJ, Briggs S, Paranka NS, et al. Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac. J Natl Cancer Inst 1995;87:1259–1260.

    PubMed  CAS  Google Scholar 

  14. Piazza GA, Alberts DS, Hixson LJ, et al. Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res 1997;57:2909–2915.

    PubMed  CAS  Google Scholar 

  15. Piazza GA, Rahm AK, Finn TS, 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;57:2452–2459.

    PubMed  CAS  Google Scholar 

  16. Piazza GA, Rahm AL, Krutzsch M, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995;55:3110–3116.

    PubMed  CAS  Google Scholar 

  17. Hixson LJ, Alberts DS, Krutzsch M, et al. Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. Cancer Epidemiol Biomark Prey 1994;3:433–438.

    CAS  Google Scholar 

  18. Han EK, Arber N, Yamamoto H, et al. Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 1998;48:195–203.

    Article  PubMed  CAS  Google Scholar 

  19. Lim JT, Piazza GA, Han EK, et al. Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Biochem Pharmacol 1999;58:1097–1107.

    Article  PubMed  CAS  Google Scholar 

  20. Thompson HJ, Jiang C, Lu J, et al. Sulfone metabolite of sulindac inhibits mammary carcinogenesis. Cancer Res 1997;57:267–271.

    PubMed  CAS  Google Scholar 

  21. Goluboff ET, Shabsigh A, Saidi JA, et al. Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. Urology 1999;53:440–445.

    Article  PubMed  CAS  Google Scholar 

  22. Whitehead CM, Earle K, Xu S, et al. CP461 in an orthotopic human NSCLC rat model involves phosphodiesterase targeting, apoptosis induction, G2M block and anti-proliferation. Proc Am Assoc Cancer Res 2002;19:924.

    Google Scholar 

  23. Whitehead CM, Earle K, Fetter J, et al. CP461 inhibits cGMP PDE activity, induces apoptosis and arrests cell cycle progression in A549 cells in culture and in an orthotopic lung tumor model. Apoptosis and Cancer: Basic Mechanisms and Therapeutic Opportunities in the Post-genomic Era. American Association for Cancer Research Meeting; Waikoloa, Hawaii. February 13–17, 2002.

    Google Scholar 

  24. Stoner GD, Budd GT, Ganapathi R, et al. Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis. Adv Exp Med Biol 1999;470:45–53.

    Article  PubMed  CAS  Google Scholar 

  25. Li H, Chen M, David M, et al. CP461, an exisulind analog regulates apoptosis using PKG and Bc1–2 mechanisms. Apoptosis and Cancer: Basic Mechanisms and Therapeutic Opportunities in the Post-genomic Era. American Association for Cancer Research Meeting; Waikoloa, Hawaii. February 13–17, 2002.

    Google Scholar 

  26. Burke C, van Stolk R, Arber N, et al. Exisulind prevents adenoma formation in familial adenomatous polyposis (FAP). Gastroenterology 2000;118:A657, abst. 3604.

    Google Scholar 

  27. Burke C. The effect of exisulind on rectal adenomas in adults with familial adenomatous polyposis. Cancer Investig 2000;19 (Suppl. 1):26–28.

    Google Scholar 

  28. Arber D, Rex D, Sjodahl R, et al. Exisulind induced regression of sporadic adenomatous polyps in a randomized, doubleblind, placebo controlled trial. Gastroenterology 2002;122 (4 Suppl 1):A70–A71.

    Google Scholar 

  29. Dousa TP. Cyclic-3′,5′-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int 1999;55:29–62.

    Article  PubMed  CAS  Google Scholar 

  30. Essayan DM. Cyclic nucleotide phosphodiesterases. JAllergy Clin Immunol 2001;108:671–680.

    Article  CAS  Google Scholar 

  31. Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. JBiol Chem 1999;274:13,729–13,732.

    Article  CAS  Google Scholar 

  32. Li L, Yee C, Beavo JA. CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science 1999;283:848–851.

    Article  PubMed  CAS  Google Scholar 

  33. Prasad KN, Becker G, Tripathy K. Differences and similarities btween guanosine 3′,5′-cyclic monophosphate phosphodiesterase and adenosine 3′,5′-cyclic monophosphate phosphodiesterase activities in neuroblastoma cells in culture. Proc Soc Exp Biol Med 1975;149:757–762.

    PubMed  CAS  Google Scholar 

  34. Marko D, Pahlke G, Merz KH, Eisenbrand G. Cyclic 3′,5′-nucleotide phosphodiesterases: potential targets for anticancer therapy. Chem Res Toxicol 2000;13:944–948.

    Article  PubMed  CAS  Google Scholar 

  35. Carrithers SL, Barber MT, Biswas S, et al. Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues. Proc Natl Acad Sci USA 1996;93:14,827–14,832.

    Article  CAS  Google Scholar 

  36. Piazza GA, Klein-Szanto AJ, Ahnen J, et al. Overexpression of cGMP phosphodiesterase (cG PDE) in colonic neoplasias compared to normal mucosa. Gastroenterology 2000;118:590.

    Article  Google Scholar 

  37. Piazza GA, Thompson WJ, Pamukcu R, et al. Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis. Cancer Res 2001;61:3961–3968.

    PubMed  CAS  Google Scholar 

  38. Piazza GA, Klein-Szanto AJ, Xu A, et al. Phosphodiesterase 5 overexpression in human non-small cell lung tumors compared to normal bronchial epithelium. Proc Am Assoc Cancer Res 2001;42,4351.

    Google Scholar 

  39. Piazza GA, Sperl G, Whitehead CM, et al. Cyclic GMP phosphodiesterase (cG PDE): overexpression in human pancreatic carcinomas and a target for selective apoptotic antineoplastic drugs. Gastroenterology 2001;120 (5 Suppl 1):140.

    Google Scholar 

  40. Thompson WJ, Piazza GA, Li H, 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;60:3338–3342.

    PubMed  CAS  Google Scholar 

  41. Soh JW, Mao Y, Kim MG, et al. Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res 2000;6:4136–4141.

    PubMed  CAS  Google Scholar 

  42. Soh JW, Mao Y, Liu L, et al. Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK 1. JBiol Chem 2001;276:16,406–16,410.

    Article  CAS  Google Scholar 

  43. Liu L, Li H, Underwood T, et al. Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. JPharmacol Exp Ther 2001;299:583–592.

    CAS  Google Scholar 

  44. Chen YR, Meyer CF, Tan TH. Persistent activation of c-Jun N-terminal kinase 1 (JNK1) in gamma radiation-induced apoptosis. JBiol Chem 1996;271:631–634.

    Article  CAS  Google Scholar 

  45. Chen YR, Wang W, Kong AN, Tan TH. Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. JBiol Chem 1998;273:1769–1775.

    Article  CAS  Google Scholar 

  46. Basu S, Kolesnick R. Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 1998;17:3277–3285.

    Article  PubMed  Google Scholar 

  47. Behrens J, von Kries JP, Kuhl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996;382:638–642.

    Article  PubMed  CAS  Google Scholar 

  48. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 2000;287:1606–1609.

    Article  PubMed  CAS  Google Scholar 

  49. Roose J, Clevers H. TCF transcription factors: molecular switches in carcinogenesis. Biochim Biophys Acta 1999;1424:M23–M37.

    PubMed  CAS  Google Scholar 

  50. Morin PJ, Sparks AB, Korinek V, et al. Activation of betacatenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787–1790.

    Article  PubMed  CAS  Google Scholar 

  51. Behrens J. Control of beta-catenin signaling in tumor development. Ann NY Acad Sci 2000;910:21–33.

    Article  PubMed  CAS  Google Scholar 

  52. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APClbeta-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998;58:1130–1134.

    PubMed  CAS  Google Scholar 

  53. Li H, Liu L, David M, et al. Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve β-catenin and cyclin D1 down regulation. Biochem Pharmacol 2002:64:1325–1336.

    Article  PubMed  CAS  Google Scholar 

  54. Whitehead CM, Fetter J, Xu S, et al. CP461, a pro-apoptotic inhibitor of cGMP phosphodiesterases (PDE), disrupts normal microtubule organization and bipolar spindle formation leading to a prometaphase mitotic block. Proc Am Assoc Cancer Res 2002;43:410, abst. 2043.

    Google Scholar 

  55. Yoon J-T, Palazzo AF, Xiao D, et al. CP248, a derivative of exisulind, causes growth inhibition, mitotic arrest, and abnormalities in microtubule polymerization in glioma cells. Mol Cancer Ther 2002;1:393–404.

    PubMed  CAS  Google Scholar 

  56. Goluboff ET. Exisulind, a selective apoptotic antineoplastic drug. Expert Opin Investig Drugs 2001;10:1875–1882.

    Article  PubMed  CAS  Google Scholar 

  57. Earle K, Piazza G, Lloyd M, et al. Effect of CP-461 on adrogen-independent (PC-3) human prostate cancer xenographs in nude mice. JUrol 2000;163 (4 Suppl):38.

    Google Scholar 

  58. Phillips RK, Hultcrantz R, Bjork J, et al. Exisulind,a pro-apoptotic drug, prevents new polyp formation in patients with familial adenomatous polyposis. Gut 2000;47:A2–A3.

    Article  Google Scholar 

  59. Goluboff ET, Prager D, Rukstalis D, et al. Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. J Urol 2001;166:882–886.

    Article  PubMed  CAS  Google Scholar 

  60. Prager D, Goluboff ET, Rukstalis D, et al. Long-term use of exisulind in men with prostate cancer following radical prostatectomy. Am Soc Clin Oncol 2002;21:abst. 733.

    Google Scholar 

  61. Alila H, Finn TS, Sperl G, et al. A pharmacokinetic and safety study of a selective apoptotic antineoplastic drug (SAAND), CP-461, in healthy volunteers. Proc Am Soc Clin Oncol 2000;19:abst 817.

    Google Scholar 

  62. Sun W, Stevenson JP, Redlinger M, et al. Phase I clinical and pharmacokinetic (PK) trial of the novel pro-apoptotic compound CP-461 administered orally on a continuous twice-daily schedule to patients with advanced malignancies. Proc Am Soc Clin Oncol 2001;20:abst 459.

    Google Scholar 

  63. Deguchi A, Soh JW, Li H, et al. Vasodilator-stimulated phosphoprotein (VASP) phosphorylation provides a biomarker for the action of exisulind and related agents that activate protein kinase G. Mol Cancer Ther 2002;1:803–809.

    PubMed  CAS  Google Scholar 

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Authors
  1. Melissa K. Reeder PhD
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  2. Rifat Pamakcu MD PhD
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  3. I. Bernard Weinstein MD
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  4. Kirk Hoffman PhD
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  5. W. Joseph Thompson PhD
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Editor information

Editors and Affiliations

  1. National Institutes of Health, Rockville, MD, USA

    Gary J. Kelloff MD  & Ernest T. Hawk MD, MPH  & 

  2. CCS Associates, Mountain View, CA, USA

    Caroline C. Sigman PhD

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© 2004 Springer Science+Business Media New York

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Reeder, M.K., Pamakcu, R., Weinstein, I.B., Hoffman, K., Thompson, W.J. (2004). Select Cyclic Nucleotide Phosphodiesterase Inhibitors in Colon Tumor Chemoprevention and Chemotherapy. In: Kelloff, G.J., Hawk, E.T., Sigman, C.C. (eds) Cancer Chemoprevention. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-767-3_28

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  • DOI: https://doi.org/10.1007/978-1-59259-767-3_28

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-342-8

  • Online ISBN: 978-1-59259-767-3

  • eBook Packages: Springer Book Archive

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