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Lymphoma

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

Leukemia volume 21, pages 2344–2353 (2007)Cite this article

Abstract

Recent reports showing successful inhibition of cancer and leukemia cell growth using histone deacetylase inhibitor (HDACi) compounds have highlighted the potential use of HDACi as anti-cancer agents. However, high incidence of toxicity and low stability in vivo were observed with hydroxamic acid-based HDACi such as suberoylanilide hydroxamic acid (SAHA), thus limiting its clinical applicability. In this study, we found that a novel non-hydroxamate HDACi NCH-51 could inhibit the cell growth of a variety of lymphoid malignant cells through apoptosis induction, more effectively than SAHA. Activation of caspase-3, -8 and -9, but not -7 was detected after the treatment with NCH-51. Gene expression profiles showed that NCH-51 and SAHA similarly upregulated p21 and downregulated anti-apoptotic molecules including survivin, bcl-w and c-FLIP. Proteome analysis using two-dimensional electrophoresis revealed that NCH-51 upregulated anti-oxidant molecules including peroxiredoxin 1 and 2 and glutathione S-transferase at the protein level. Interestingly, NCH-51 induced reactive oxygen species (ROS) after 8 h whereas SAHA continuously declined ROS. Pretreatment with an antioxidant, N-acetyl-L-cysteine, abolished the cytotoxicity of NCH-51. These findings suggest that NCH-51 exhibits cytotoxicity by sustaining ROS at the higher level greater than SAHA. This study indicates the therapeutic efficacy of NCH-51 and novel insights for anti-HDAC therapy.

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References

  1. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    Article  CAS  Google Scholar 

  2. Strahl BD, Allis CD . The language of covalent histone modifications. Nature 2000; 403: 41–45.

    Article  CAS  Google Scholar 

  3. Turner BM . Cellular memory and the histone code. Cell 2002; 111: 285–291.

    Article  CAS  Google Scholar 

  4. Claus R, Lubbert M . Epigenetic targets in hematopoietic malignancies. Oncogene 2003; 22: 6489–6496.

    Article  CAS  Google Scholar 

  5. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005; 37: 391–400.

    Article  CAS  Google Scholar 

  6. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005; 435: 1262–1266.

    Article  CAS  Google Scholar 

  7. Kelly WK, Marks PA . Drug insight: histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2005; 2: 150–157.

    Article  CAS  Google Scholar 

  8. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923–3931.

    Article  CAS  Google Scholar 

  9. Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J et al. 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 2005; 23: 3912–3922.

    Article  CAS  Google Scholar 

  10. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T . Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998; 12: 12–26.

    Article  CAS  Google Scholar 

  11. Suzuki T, Nagano Y, Kouketsu A, Matsuura A, Maruyama S, Kurotaki M et al. Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates. J Med Chem 2005; 48: 1019–1032.

    Article  CAS  Google Scholar 

  12. Huang L, Sowa Y, Sakai T, Pardee AB . Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 2000; 19: 5712–5719.

    Article  CAS  Google Scholar 

  13. Richon VM, Sandhoff TW, Rifkind RA, Marks PA . Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 2000; 97: 10014–10019.

    Article  CAS  Google Scholar 

  14. Rosato RR, Almenara JA, Grant S . The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 2003; 63: 3637–3645.

    CAS  PubMed  Google Scholar 

  15. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005; 280: 26729–26734.

    Article  CAS  Google Scholar 

  16. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A et al. HDAC6 is a microtubule-associated deacetylase. Nature 2002; 417: 455–458.

    Article  CAS  Google Scholar 

  17. Insinga A, Monestiroli S, Ronzoni S, Carbone R, Pearson M, Pruneri G et al. Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J 2004; 23: 1144–1154.

    Article  CAS  Google Scholar 

  18. Chen L, Fischle W, Verdin E, Greene WC . Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001; 293: 1653–1657.

    Article  CAS  Google Scholar 

  19. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102: 8567–8572.

    Article  CAS  Google Scholar 

  20. Sanda T, Asamitsu K, Ogura H, Iida S, Utsunomiya A, Ueda R et al. Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. Leukemia 2006; 20: 590–598.

    Article  CAS  Google Scholar 

  21. Uranishi M, Iida S, Sanda T, Ishida T, Tajima E, Ito M et al. Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy. Leukemia 2005; 19: 1471–1478.

    Article  CAS  Google Scholar 

  22. Pulvertaft JV . Cytology of Burkitt’s tumour (African lymphoma). Lancet 1964; 39: 238–240.

    Article  Google Scholar 

  23. Klein E, Klein G, Nadkarni JS, Nadkarni JJ, Wigzell H, Clifford P . Surface IgM-kappa specificity on a Burkitt lymphoma cell in vivo and in derived culture lines. Cancer Res 1968; 28: 1300–1310.

    CAS  PubMed  Google Scholar 

  24. Suzuki A, Iida S, Kato-Uranishi M, Tajima E, Zhan F, Hanamura I et al. ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene 2005; 24: 6936–6944.

    Article  CAS  Google Scholar 

  25. Sanda T, Iida S, Ogura H, Asamitsu K, Murata T, Bacon KB et al. Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. Clin Cancer Res 2005; 11: 1974–1982.

    Article  CAS  Google Scholar 

  26. Seike M, Kondo T, Mori Y, Gemma A, Kudoh S, Sakamoto M et al. Proteomic analysis of intestinal epithelial cells expressing stabilized beta-catenin. Cancer Res 2003; 63: 4641–4647.

    CAS  PubMed  Google Scholar 

  27. Imai K, Nakata K, Kawai K, Hamano T, Mei N, Kasai H et al. Induction of OGG1 gene expression by HIV-1 Tat. J Biol Chem 2005; 280: 26701–26713.

    Article  CAS  Google Scholar 

  28. Opferman JT, Korsmeyer SJ . Apoptosis in the development and maintenance of the immune system. Nat Immunol 2003; 4: 410–415.

    Article  CAS  Google Scholar 

  29. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003; 115: 727–738.

    Article  CAS  Google Scholar 

  30. Song EJ, Kim YS, Chung JY, Kim E, Chae SK, Lee KJ . Oxidative modification of nucleoside diphosphate kinase and its identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Biochemistry 2000; 39: 10090–10097.

    Article  CAS  Google Scholar 

  31. Arnaud-Dabernat S, Masse K, Smani M, Peuchant E, Landry M, Bourbon PM et al. Nm23-M2/NDP kinase B induces endogenous c-myc and nm23-M1/NDP kinase A overexpression in BAF3 cells. Both NDP kinases protect the cells from oxidative stress-induced death. Exp Cell Res 2004; 301: 293–304.

    Article  CAS  Google Scholar 

  32. Harrop SJ, DeMaere MZ, Fairlie WD, Reztsova T, Valenzuela SM, Mazzanti M et al. Crystal structure of a soluble form of the intracellular chloride ion channel CLIC1 (NCC27) at 1.4-A resolution. J Biol Chem 2001; 276: 44993–45000.

    Article  CAS  Google Scholar 

  33. Shimizu T, Numata T, Okada Y . A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl(−) channel. Proc Natl Acad Sci USA 2004; 101: 6770–6773.

    Article  CAS  Google Scholar 

  34. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci USA 2001; 98: 10833–10838.

    Article  CAS  Google Scholar 

  35. Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005; 102: 673–678.

    Article  CAS  Google Scholar 

  36. Yokomizo A, Ono M, Nanri H, Makino Y, Ohga T, Wada M et al. Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Res 1995; 55: 4293–4296.

    CAS  PubMed  Google Scholar 

  37. Ryazanov AG, Shestakova EA, Natapov PG . Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 1988; 334: 170–173.

    Article  CAS  Google Scholar 

  38. Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG . Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors. Eur J Biochem 2002; 269: 3076–3085.

    Article  CAS  Google Scholar 

  39. Young JC, Agashe VR, Siegers K, Hartl FU . Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 2004; 5: 781–791.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Mr ME Cueno for language editing. This work is supported in part by grant-in-aids from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan. TS is supported by a grant of Aichi Cancer Research Foundation and a grant of Oujinkai Foundation. HN, TS and NY are supported by a grant of Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    T Sanda, T Okamoto & Y Uchida

  2. Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    T Sanda, S Iida, S Kayukawa & R Ueda

  3. Department of Organic and Medicinal Chemistry, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan

    H Nakagawa, T Suzuki & N Miyata

  4. Department of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan

    T Oshizawa & T Suzuki

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  1. T Sanda
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Correspondence to T Okamoto.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Sanda, T., Okamoto, T., Uchida, Y. et al. Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells. Leukemia 21, 2344–2353 (2007). https://doi.org/10.1038/sj.leu.2404902

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