Skip to main content

Advertisement

SpringerLink
Log in

Epigenetic therapy of lymphoma using histone deacetylase inhibitors

  • Educational Series
  • Molecular Targets in Oncology
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

In this study, we reviewed epigenetic therapy of lymphomas using histone deacetylase inhibitors (HDACi), a promising new class of antineoplastic agents. Epigenetic therapy, a new therapeutic concept, consists of the use of HDACi and or DNA methyltransferase inhibitors (DNMTi). We conducted a comprehensive review of the literature for antitumour activity of HDACi and its mechanism of action. HDACi modify the expression of several genes related to cancer development, which can result in antineoplastic activity. To elucidate the benefits of HDACi in lymphoma treatment, we discuss the crucial interplay between BCL6, p53 and STAT3. Activated B-cell (ABC) diffuse large cell lymphoma (DLCL) is increasingly being recognised as an unfavourable and frequently therapy-refractory lymphoma. We discuss the fundamental causative role of the STAT3 oncogene in ABC type DLCL. STAT3 can be effectively suppressed by several HDACi, a promising treatment for this difficult subtype of DLCL. On the other hand, various HDACi can repress the germinal-centre B Cell (GCB) type DLCL by virtue of their inhibition of the BCL6 oncogene, usually expressed in this particular subtype. We summarise the results of recent clinical trials with HDACi such as romidepsin, panobinostat, MGCD-0103, entinostat, curcumin, JAK2 inhibitor TG101348, and valproic acid that have shown preliminary activity in recurrent and refractory lymphomas. The unique mechanism of action of HDACi makes them very attractive agents to pursue in combination. Several ongoing trials are already exploring HDACi combinations in various types of cancers. Their role in front-line management remains to be determined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Brueckner B, Lyko F (2004) DNA methyltransferase inhibitors: old and new drugs for an epigenetic cancer therapy. Trends Pharmacol Sci 25:551–554

    Article  CAS  PubMed  Google Scholar 

  3. Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349–352

    Article  CAS  PubMed  Google Scholar 

  4. Marks PA, Xu WS (2009) Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem 107:600–608

    Article  CAS  PubMed  Google Scholar 

  5. Dokmanovic M, Marks PA (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96:293–304

    Article  CAS  PubMed  Google Scholar 

  6. Glaser KB, Staver MJ, Waring JF et al (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151–163

    CAS  PubMed  Google Scholar 

  7. Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    Article  CAS  PubMed  Google Scholar 

  8. Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511

    Article  CAS  PubMed  Google Scholar 

  9. Chang CC, McClintock S, Cleveland RP et al (2004) Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma. Am J Surg Pathol 28:464–470

    Article  PubMed  Google Scholar 

  10. Mogal A, Abdulkadir SA (2006) Effects of histone deacetylase inhibitor (HDACi) trichostatin-A (TSA) on the expression of housekeeping genes. Mol Cell Probes 20:81–86

    Article  CAS  PubMed  Google Scholar 

  11. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  CAS  PubMed  Google Scholar 

  12. Esteller M, Almouzni G (2005) How epigenetics integrates nuclear functions. Workshop on epigenetics and chromatin: transcriptional regulation and beyond. EMBO Rep 6:624–628

    Article  CAS  PubMed  Google Scholar 

  13. Fraga MF, Ballestar E, Villar-Garea A et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400

    Article  CAS  PubMed  Google Scholar 

  14. Walkinshaw DR, Yang XJ (2008) Histone deacetylase inhibitors as novel anticancer therapeutics. Curr Oncol 15:237–243

    CAS  PubMed  Google Scholar 

  15. Lee KH, Lotterman C, Karikari C et al (2009) Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 9:293–301

    Article  CAS  PubMed  Google Scholar 

  16. Bai M, Skyrlas A, Agnantis NJ et al (2004) Cluster analysis of apoptosis-associated bcl2 family proteins in diffuse large B-cell lymphomas. Relations with the apoptotic index, the proliferation profile and the B-cell differentiation immunophenotypes. Anticancer Res 24:3081–3088

    CAS  PubMed  Google Scholar 

  17. Bai M, Papoudou-Bai A, Horianopoulos N et al (2007) Expression of bcl2 family proteins and active caspase 3 in classical Hodgkin’s lymphomas. Hum Pathol 38:103–113

    Article  CAS  PubMed  Google Scholar 

  18. Peart MJ, Smyth GK, van Laar RK et al (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102:3697–702

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Ju R, Muller MT (2003) Histone deacetylase inhibitors activate p21(WAF1) expression via ATM. Cancer Res 63:2891–2897

    CAS  PubMed  Google Scholar 

  21. Lindemann RK, Johnstone RW (2004) Histone deacetylase inhibitors: promising candidates for chemotherapeutic drugs. Gene Ther Mol Biol 8:61–74

    Google Scholar 

  22. Mullauer L, Mosberger I, Chott A (1998) Fas ligand expression in nodal non-Hodgkin’s lymphoma. Mod Pathol 11:369–375

    CAS  PubMed  Google Scholar 

  23. Kwon SH, Ahn SH, Kim YK et al (2002) Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J Biol Chem 277:2073–2080

    Article  CAS  PubMed  Google Scholar 

  24. Yamanegi K, Yamane J, Hata M et al (2009) Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death. J Cancer Res Clin Oncol 135:879–889

    Article  CAS  PubMed  Google Scholar 

  25. Lindemann RK, Newbold A, Whitecross KF et al (2007) Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc Natl Acad Sci U S A 104:8071–8076

    Article  CAS  PubMed  Google Scholar 

  26. Chen J, Ghazawi FM, Bakkar W et al (2006) Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B. Mol Cancer 5:71

    Article  CAS  PubMed  Google Scholar 

  27. Phan RT, Dalla-Favera R (2004) The BCL6 protooncogene suppresses p53 expression in germinalcentre B cells. Nature 432:635–639

    Article  CAS  PubMed  Google Scholar 

  28. Lemercier C, Brocard MP, Puvion-Dutilleul F et al (2002) Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. J Biol Chem 277:22045–22052

    Article  CAS  PubMed  Google Scholar 

  29. Kerckaert JP, Deweindt C, Tilly H et al (1993) LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet 5:66–70

    Article  CAS  PubMed  Google Scholar 

  30. O’Connor OA (2005) Targeting Histones and Proteasomes: New Strategies for the Treatment of Lymphoma. J Clin Oncol 23:6429–6436

    Article  PubMed  Google Scholar 

  31. Ci W, Polo JM, Melnick A (2008) B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma. Curr Opin Hematol 15:381–390

    Article  CAS  PubMed  Google Scholar 

  32. Lo Coco F, Ye BH, Lista F et al (1994) Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin’s lymphoma. Blood 83:1757–1759

    PubMed  Google Scholar 

  33. Ding BB, Yu JJ, Yu RY et al (2008) Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 111: 1515–1523

    Article  CAS  PubMed  Google Scholar 

  34. Amaravadi RK, Thompson CB (2007) The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 13:7271–7279

    Article  CAS  PubMed  Google Scholar 

  35. Amaravadi RK, Yu D, Lum JJ et al (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117:326–336

    Article  CAS  PubMed  Google Scholar 

  36. Carew JS, Nawrocki ST, Giles FJ et al (2008) Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance. Biologics 2:201–204

    CAS  PubMed  Google Scholar 

  37. Oh M, Choi IK, Kwon HJ (2008) Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun 369:1179–1183

    Article  CAS  PubMed  Google Scholar 

  38. Martin AP, Park MA, Mitchell C et al (2009) BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing. Mol Pharmacol 76:327–341

    Article  CAS  PubMed  Google Scholar 

  39. Carew JS, Medina EC, Esquivel JA 2nd et al (2009) Autophagy inhibition enhances vorinostatinduced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med [Epub ahead of print]

  40. Gupta M, Stenson M, Lasho T et al (2009) Interplay between histone deacetylases (HDACs) and STAT3: mechanism of activated JAK/STAT3 oncogenic pathway in ABC (activated B-cell)-type diffuse large B cell lymphoma. ASH Annual Meeting Abstracts 114:925

    Google Scholar 

  41. Pasqualucci L, Bereschenko O, Niu H et al (2003) Molecular pathogenesis of non-Hodgkin’s lymphoma: the role of Bcl-6. Leuk Lymphoma 44(Suppl 3):S5–S12

    Article  CAS  PubMed  Google Scholar 

  42. Gurvich N, Tsygankova OM, Meinkoth JL et al (2004) Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 64:1079–1086

    Article  CAS  PubMed  Google Scholar 

  43. Kawagoe R, Kawagoe H, Sano K (2002) Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res 26:495–502

    Article  CAS  PubMed  Google Scholar 

  44. Fedier A, Dedes KJ, Imesch P et al (2007) The histone deacetylase inhibitors suberoylanilide hydroxamic (vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells. Int J Oncol 31:633–641

    CAS  PubMed  Google Scholar 

  45. Friedmann I, Atmaca A, Chow KU et al (2006) Synergistic effects of valproic acid and mitomycin C in adenocarcinoma cell lines and fresh tumor cells of patients with colon cancer. J Chemother 18:415–420

    CAS  PubMed  Google Scholar 

  46. Jones J, Bentas W, Blaheta RA et al (2008) Modulation of adhesion and growth of colon and pancreatic cancer cells by the histone deacetylase inhibitor valproic acid. Int J Mol Med 22:293–299

    CAS  PubMed  Google Scholar 

  47. Platta CS, Greenblatt DY, Kunnimalaiyaan M et al (2008) Valproic acid induces Notch1 signaling in small cell lung cancer cells. J Surg Res 148:31–37

    Article  CAS  PubMed  Google Scholar 

  48. Kortenhorst MS, Isharwal S, van Diest PJ et al (2009) Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo. Mol Cancer Ther 8:802–808

    Article  CAS  PubMed  Google Scholar 

  49. Chen CL, Sung J, Cohen M et al (2006) Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther 319:533–542

    Article  CAS  PubMed  Google Scholar 

  50. Sharma S, Symanowski J, Wong B et al (2008) A phase II clinical trial of oral valproic acid in patients with castration-resistant prostate cancers using an intensive biomarker sampling strategy. Transl Oncol 1:141–147

    PubMed  Google Scholar 

  51. Zhu S, Denman CJ, Lee DA (2009) Valproic acid selectively inhibits STAT3 phosphorylation. ASH Annual Meeting Abstracts 114:1720

    Google Scholar 

  52. Velasquez WS, McLaughlin P, Tucker S et al (1994) ESHAP-An effective chemotherapy regimen in refractory and relapsing lymphoma: A 4 year follow-up study. J Clin Oncol 12:1169–1176

    CAS  PubMed  Google Scholar 

  53. Kewalramani T, Zelenetz AD, Nimer SD et al (2004) Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103:3684–3688

    Article  CAS  PubMed  Google Scholar 

  54. Zain J, Rotter A, Weiss L et al (2007) Valproic acid monotherapy leads to CR in a patient with refractory diffuse large B cell lymphoma. Leuk Lymphoma 48:1216–1218

    Article  CAS  PubMed  Google Scholar 

  55. Stamatopoulos B, Meuleman N, De Bruyn C et al (2009) Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Leukemia 23(12):2281–2289

    Article  CAS  PubMed  Google Scholar 

  56. Bokelmann I, Mahlknecht U (2008) Valproic acid sensitizes chronic lymphocytic leukemia cells to apoptosis and restores the balance between proand antiapoptotic proteins. Mol Med 14:20–27

    Article  CAS  PubMed  Google Scholar 

  57. P. Ganesan VR, R. Kumar (2009) A phase II pilot study of valproic acid in relapsed/refractory chronic lymphocytic leukemia. ASCO Meeting Abstract 7081

  58. Duvic M, Vu J (2007) Vorinostat in cutaneous T-cell lymphoma. Drugs Today (Barc) 43:585–599

    Article  CAS  Google Scholar 

  59. Duvic M, Talpur R, Ni X et al (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31–39

    Article  CAS  PubMed  Google Scholar 

  60. Mazumder A, Vesole DH, Jagannath S (2008) Treatment of multiple myeloma with vorinostat in combination with bortezomib: a case series. ASH Annual Meeting Abstracts 112:5213

    Google Scholar 

  61. Garcia-Manero G, Silverman LB, Gojo I et al (2008) A randomized phase IIa study of vorinostat in patients with low or intermediate-1 risk myelodysplastic syndromes: preliminary results. ASH Annual Meeting Abstracts 112:5084

    Google Scholar 

  62. Kirschbaum M, Popplewell L, Auayporn P et al (2008) A phase 2 study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed or refractory indolent non-Hodgkin’s lymphoma. A California Cancer Consortium study. ASH Annual Meeting Abstract 1564

  63. Crump M, Coiffier B, Jacobsen ED et al (2008) Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol 19:964–969

    Article  CAS  PubMed  Google Scholar 

  64. Watanabe T, Kato H, Kobayashi Y et al (2009) Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci 101(1):196–200

    Article  PubMed  Google Scholar 

  65. Cultrera JL, Rosenberg L, McConkey DJ et al (2008) The Histone Deacetylase Inhibitor Vorinostat Induces Apoptosis in T-Cell Lymphoma Cell Lines and Synergizes with Bortezomib. ASH Annual Meeting Abstracts 112:1587

    Google Scholar 

  66. Weber DM, Jagannath S, Sobecks R et al (2008) Combination of vorinostat plus bortezomib for the treatment of patients with multiple myeloma who have previously received bortezomib. ASH Annual Meeting Abstracts 112:3711

    Google Scholar 

  67. Bates S, Piekarz R, Wright J et al (2008) Final clinical results of a phase 2 NCI multicenter study of romidepsin in recurrent cutaneous T-cell lymphoma (molecular analyses included). ASH Annual Meeting Abstracts 112:1568

    Google Scholar 

  68. Demierre M, Whittaker, S, Kim, Y et al (2009) Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma. Asco Annual Meeting. Abstract 8546:445

    Google Scholar 

  69. Revill P, Mealy N, Serradell N et al (2007) Panobinostat. Drugs Future 32:315

    Article  CAS  Google Scholar 

  70. Dickinson M, Ritchie D, Deangelo DJ et al (2009) Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol 147(1):97–101

    Article  CAS  PubMed  Google Scholar 

  71. Rao R, Ficus WC, Yang Y et al (2009) Targeting autophagy induced by pan-HDAC inhibitor panobinostat and promoted by acetylated hsp70: A novel therapy for breast cancer. Mol Cancer Ther 8 (Meeting Abstract Supplement): doi: 10.1158/1535-7163.TARG-09-B21

  72. Fournel M, Bonfils C, Hou Y et al (2008) MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:759–768

    Article  CAS  PubMed  Google Scholar 

  73. Garcia-Manero G, Assouline S, Cortes J et al (2008) Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112:981–989

    Article  CAS  PubMed  Google Scholar 

  74. Younes A, Pro B, Fanale M et al (2007) Isotypeselective HDAC inhibitor MGCD0103 decreases serum TARC concentrations and produces clinical responses in heavily pretreated patients with relapsed classical Hodgkin lymphoma (HL). ASH Annual Meeting Abstracts 110:2566

    Google Scholar 

  75. Gore L, Rothenberg ML, O’Bryant CL et al (2008) A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res 14:4517–4525

    Article  CAS  PubMed  Google Scholar 

  76. Liu HL, Chen Y, Cui GH et al (2005) Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta Pharmacol Sin 26:603–609

    Article  CAS  PubMed  Google Scholar 

  77. Li ZX, Ouyang KQ, Jiang X et al (2009) Curcumin induces apoptosis and inhibits growth of human Burkitt’s lymphoma in xenograft mouse model. Mol Cells 27:283–289

    Article  CAS  PubMed  Google Scholar 

  78. Cheng AL, Hsu CH, Lin JK et al (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900

    CAS  PubMed  Google Scholar 

  79. Mackenzie GG, Queisser N, Wolfson ML et al (2008) Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-kappaB and STAT3 pathways in Hodgkin’s lymphoma cells. Int J Cancer 123:56–65

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematology-Medical Oncology Section, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan, 00936-5067, Puerto Rico

    Maribel Cotto, María V. García & Eileen Pacheco

  2. Auxilio Mutuo Cancer Center, San Juan, Puerto Rico

    Fernando Cabanillas

  3. Medical Sciences Campus, University of Puerto Rico Cancer Center, San Juan, Puerto Rico

    Maribel Tirado

Authors
  1. Maribel Cotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernando Cabanillas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maribel Tirado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María V. García
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eileen Pacheco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maribel Cotto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cotto, M., Cabanillas, F., Tirado, M. et al. Epigenetic therapy of lymphoma using histone deacetylase inhibitors. Clin Transl Oncol 12, 401–409 (2010). https://doi.org/10.1007/s12094-010-0527-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-010-0527-3

Keywords

Search

Navigation