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Polyamines pp 475-491 | Cite as

Use of Polyamine Derivatives as Selective Histone Deacetylase Inhibitors

  • Patrick M. Woster
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 720)

Abstract

Histone acetylation and deacetylation, mediated by histone acetyltransferase and the 11 isoforms of histone deacetylase, play an important role in gene expression. Histone deacetylase inhibitors have found utility in the treatment of cancer by promoting the reexpression of aberrantly silenced genes that code for tumor suppressor factors. It is unclear which of the 11 histone deacetylase isoforms are important in human cancer. We have designed a series of polyaminohydroxamic acid (PAHA) and polyaminobenzamide (PABA) histone deacetylase inhibitors that exhibit selectivity among four histone deacetylase isoforms. Although all of the active inhibitors promote reexpression of tumor suppressor factors, they produce variable cellular effects ranging from stimulation of growth to cytostasis and cytotoxicity. This chapter describes the procedures used to quantify the global and isoform-specific inhibition caused by these inhibitors, and techniques used to measure cellular effects such as reexpression of tumor suppressor proteins and hyperacetylation of histones H3 and H4. Procedures are also described to examine the ability of PAHAs and PABAs to utilize the polyamine transport system and to induce overexpression of the early apoptotic factor annexin A1.

Key words

Histone deacetylase Polyaminohydroxamic acid Polyaminobenzamide Annexin A1 Polyamine transport Breast cancer 

References

  1. 1.
    Marks PA, Richon VM, Breslow R, Rifkind RA (2001) Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 13:477–483PubMedCrossRefGoogle Scholar
  2. 2.
    Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389:251–260PubMedCrossRefGoogle Scholar
  3. 3.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedCrossRefGoogle Scholar
  4. 4.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054PubMedCrossRefGoogle Scholar
  5. 5.
    Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20:3139–3155PubMedCrossRefGoogle Scholar
  6. 6.
    Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299PubMedCrossRefGoogle Scholar
  7. 7.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202PubMedCrossRefGoogle Scholar
  8. 8.
    Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL (2006) Histone H4-K16 acetylation controls chromatin ­structure and protein interactions. Science 311(5762):844–847PubMedCrossRefGoogle Scholar
  9. 9.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42PubMedCrossRefGoogle Scholar
  10. 10.
    Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262:75–83PubMedCrossRefGoogle Scholar
  11. 11.
    Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411PubMedCrossRefGoogle Scholar
  12. 12.
    Grozinger CM, Schreiber SL (2002) Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 9:3–16PubMedCrossRefGoogle Scholar
  13. 13.
    Weinmann H, Ottow E (2004) Recent advances in the medicinal chemistry of histone deacetylase inhibitors. Ann Rep Med Chem 39:185–196CrossRefGoogle Scholar
  14. 14.
    Kouraklis G, Theocharis S (2006) Histone deacetylase inhibitors: a novel target of anticancer therapy (review). Oncol Rep 15:489–494PubMedGoogle Scholar
  15. 15.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103–107PubMedCrossRefGoogle Scholar
  16. 16.
    Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB (1997) Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 57:837–841PubMedGoogle Scholar
  17. 17.
    Herman JG, Jen J, Merlo A, Baylin SB (1996) Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56:722–727PubMedGoogle Scholar
  18. 18.
    Corn PG, Smith BD, Ruckdeschel ES, Douglas D, Baylin SB, Herman JG (2000) E-cadherin expression is silenced by 5’ CpG island methylation in acute leukemia. Clin Cancer Res 6:4243–4248PubMedGoogle Scholar
  19. 19.
    Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, Figg WD, Hwang K, Chung EJ, Murgo A, Melillo G, Elsayed Y, Monga M, Kalnitskiy M, Zwiebel J, Sausville EA (2005) Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23:3912–3922PubMedCrossRefGoogle Scholar
  20. 20.
    Varghese S, Gupta D, Baran T, Jiemjit A, Gore SD, Casero RA Jr, Woster PM (2005) Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors. J Med Chem 48:6350–6365PubMedCrossRefGoogle Scholar
  21. 21.
    Varghese S, Senanayake T, Murray-Stewart T, Doering K, Fraser A, Casero RA, Woster PM (2008) Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors. J Med Chem 51:2447–2456PubMedCrossRefGoogle Scholar
  22. 22.
    Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458PubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, Yamashita T, Nakanishi O (1999) Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives­. J Med Chem 42:3001–3003PubMedCrossRefGoogle Scholar
  24. 24.
    Casero RA Jr, Woster PM (2009) Recent advances in the development of polyamine analogues as antitumor agents. J Med Chem 52:4551–4573PubMedCrossRefGoogle Scholar
  25. 25.
    Seiler N, Delcros JG, Moulinoux JP (1996) Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol 28:843–861PubMedCrossRefGoogle Scholar
  26. 26.
    Tabe Y, Jin L, Contractor R, Gold D, Ruvolo P, Radke S, Xu Y, Tsutusmi-Ishii Y, Miyake K, Miyake N, Kondo S, Ohsaka A, Nagaoka I, Andreeff M, Konopleva M (2007) Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1. Cell Death Differ 14:1443–1456PubMedCrossRefGoogle Scholar
  27. 27.
    Chuthapisith S, Bean BE, Cowley G, Eremin JM, Samphao S, Layfield R, Kerr ID, Wiseman J, El-Sheemy M, Sreenivasan T, Eremin O (2009) Annexins in human breast cancer: Possible predictors of pathological response to neoadjuvant chemotherapy. European Journal of Cancer 45(7):1274–81PubMedCrossRefGoogle Scholar
  28. 28.
    Gowri PM, Yu JH, Shaufl A, Sperling MA, Menon RK (2003) Recruitment of a repressosome complex at the growth hormone receptor promoter and its potential role in diabetic nephropathy. Mol Cell Biol 23:815–825PubMedCrossRefGoogle Scholar
  29. 29.
    Miao F, Gonzalo IG, Lanting L, Natarajan R (2004) In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem 279:18091–18097PubMedCrossRefGoogle Scholar
  30. 30.
    Gray SG, De Meyts P (2005) Role of histone and transcription factor acetylation in diabetes pathogenesis. Diab Metab Res Rev 21:416–433CrossRefGoogle Scholar
  31. 31.
    Lee HB, Noh H, Seo JY, Yu MR, Ha H (2007) Histone deacetylase inhibitors: a novel class of therapeutic agents in diabetic nephropathy. Kidney Int Suppl (106):S61–S66Google Scholar
  32. 32.
    Susick L, Senanayake T, Veluthakal R, Woster PM, Kowluru A (2009) A novel histone deacetylase inhibitor prevents IL-1beta-induced metabolic dysfunction in pancreatic beta-cells. J Cell Mol Med 13(8B):1877–85PubMedCrossRefGoogle Scholar
  33. 33.
    Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, Newgard CB (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49:424–430PubMedCrossRefGoogle Scholar
  34. 34.
    Aziz SM, Yatin M, Worthen DR, Lipke DW, Crooks PA (1998) A novel technique for visualizing the intracellular localization and distribution of transported polyamines in cultured pulmonary artery smooth muscle cells. J Pharm Biomed Anal 17:307–320PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Patrick M. Woster
    • 1
  1. 1.Department of Pharmaceutical SciencesWayne State UniversityDetroitUSA

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