Skip to main content
SpringerLink
Log in

Histone Deacetylase Inhibitors

Current Status and Overview of Recent Clinical Trials

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Histone deacetylase (HDAC) inhibitors are a new group of anticancer agents that have a potential role in the regulation of gene expression, induction of cell death, apoptosis and cell cycle arrest of cancer cells by altering the acetylation status of chromatin and other non-histone proteins. In clinical trials, HDAC inhibitors have demonstrated promising antitumour activity as monotherapy in cutaneous T-cell lymphoma and other haematological malignancies. In solid tumours, several HDAC inhibitors have been shown to be efficacious as single agents; however, results of most clinical trials were in favour of using HDAC inhibitors either prior to the initiation of chemotherapy or in combination with other treatments. Currently, the molecular basis of response to HDAC inhibitors in patients is not fully understood. In this review, we summarize the current status of HDAC inhibitors, as single agents or in combination with other agents in different phases of clinical trials. In most of the clinical trials, HDAC inhibitors were tolerable and exerted biological or antitumor activity. HDAC inhibitors have been studied in phase I, II and III clinical trials with variable efficacy. The combination of HDAC inhibitors with other anticancer agents including epigenetic or chemotherapeutic agents demonstrated favourable clinical outcome.

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

Fig. 1
Table I
Table II
Fig. 2
Table III
Table IV

Similar content being viewed by others

References

  1. Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008 Feb 1; 111(3): 1060–6

    Article  PubMed  CAS  Google Scholar 

  2. Klimek VM, Fircanis S, Maslak P, et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelo-genous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res 2008 Feb 1; 14(3): 826–32

    Article  PubMed  CAS  Google Scholar 

  3. Byrd JC, Marcucci G, Parthun MR, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 2005 Feb 1; 105(3): 959–67

    Article  PubMed  CAS  Google Scholar 

  4. Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 2007 Sep 1; 25(25): 3884–91

    Article  PubMed  CAS  Google Scholar 

  5. Piekarz RL, Sackett DL, Bates SE. Histone deacetylase inhibitors and demethylating agents: clinical development of histone deacetylase inhibitors for cancer therapy. Cancer J 2007 Jan-Feb; 13(1): 30–9

    Article  PubMed  CAS  Google Scholar 

  6. Shen L, Issa JP. Epigenetics in colorectal cancer. Curr Opin Gastroenterol 2002 Jan; 18(1): 68–73

    Article  PubMed  CAS  Google Scholar 

  7. Agrawal A, Murphy RF, Agrawal DK. DNA methylation in breast and colorectal cancers. Mod Pathol 2007 Jul; 20(7): 711–21

    Article  PubMed  CAS  Google Scholar 

  8. Mariadason JM. HDACs and HDAC inhibitors in colon cancer. Epigenetics 2008 Jan-Feb; 3(1): 28–37

    Article  PubMed  Google Scholar 

  9. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene 2007 Aug 13; 26(37): 5420–32

    Article  PubMed  CAS  Google Scholar 

  10. Toyota M, Suzuki H, Yamashita T, et al. Cancer epigenomics: implications of DNA methylation in personalized cancer therapy. Cancer Sci 2009 May; 100(5): 787–91

    Article  PubMed  CAS  Google Scholar 

  11. Mahlknecht U, Hoelzer D. Histone acetylation modifiers in the pathogenesis of malignant disease. Mol Med 2000 Aug; 6(8): 623–44

    PubMed  CAS  Google Scholar 

  12. Santos-Rosa H, Caldas C. Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer 2005 Nov; 41(16): 2381–402

    Article  PubMed  CAS  Google Scholar 

  13. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007 Feb 23; 128(4): 683–92

    Article  PubMed  CAS  Google Scholar 

  14. Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005 Apr; 37(4): 391–400

    Article  PubMed  CAS  Google Scholar 

  15. Lafon-Hughes L, Di Tomaso MV, Mendez-Acuna L, et al. Chromatin-remodelling mechanisms in cancer. Mutat Res 2008 Mar–Apr; 658(3): 191–214

    Article  PubMed  CAS  Google Scholar 

  16. Ishihama K, Yamakawa M, Semba S, et al. Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J Clin Pathol 2007 Nov; 60(11): 1205–10

    Article  PubMed  CAS  Google Scholar 

  17. Yang XJ, Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 2007 Aug 13; 26(37): 5310–8

    Article  PubMed  CAS  Google Scholar 

  18. Acharya MR, Sparreboom A, Venitz J, et al. Rational development of histone deacetylase inhibitors as anti-cancer agents: a review. Mol Pharmacol 2005 Oct; 68(4): 917–32

    Article  PubMed  CAS  Google Scholar 

  19. Iyer NG, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene 2004 May 24; 23(24): 4225–31

    Article  PubMed  CAS  Google Scholar 

  20. Kitabayashi I, Aikawa Y, Yokoyama A, et al. Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p1 1;q13) chromosome translocation. Leukemia 2001 Jan; 15(1): 89–94

    Article  PubMed  CAS  Google Scholar 

  21. Rozman M, Camos M, Colomer D, et al. Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation. Genes Chromosomes Cancer 2004 Jun; 40(2): 140–5

    Article  PubMed  CAS  Google Scholar 

  22. Crowley JA, Wang Y, Rapoport AP, et al. Detection of MOZ-CBP fusion in acute myeloid leukemia with 8; 16 translocation. Leukemia 2005 Dec; 19(12): 2344–5

    Article  PubMed  CAS  Google Scholar 

  23. Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004 May 27; 429(6990): 457–63

    Article  PubMed  CAS  Google Scholar 

  24. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 2007 Aug 13; 26(37): 5541–52

    Article  PubMed  CAS  Google Scholar 

  25. Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008 Sep 28; 269(1): 7–17

    Article  PubMed  CAS  Google Scholar 

  26. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 2007 Oct; 5(10): 981–9

    Article  PubMed  CAS  Google Scholar 

  27. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Disc 2006 Sep; 5(9): 769–84

    Article  CAS  Google Scholar 

  28. Dokmanovic M, Marks PA. Prospects: histone deacetylase inhibitors. J Cell Biochem 2005 Oct 1; 96(2): 293–304

    Article  PubMed  CAS  Google Scholar 

  29. Fouladi M. Histone deacetylase inhibitors in cancer therapy. Cancer Invest 2006 Aug-Sep; 24(5): 521–7

    Article  PubMed  CAS  Google Scholar 

  30. Mann BS, Johnson JR, Cohen MH, et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007 Oct; 12(10): 1247–52

    Article  PubMed  CAS  Google Scholar 

  31. Glaser KB. HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 2007 Sep 1; 74(5): 659–71

    Article  PubMed  CAS  Google Scholar 

  32. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007 Jan 1; 109(1): 31–9

    Article  PubMed  CAS  Google Scholar 

  33. Crump M, Coiffier B, Jacobsen ED, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol 2008 May; 19(5): 964–9

    Article  PubMed  CAS  Google Scholar 

  34. Modesitt SC, Sill M, Hoffman JS, et al. A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecol Oncol Group study. Gynecol Oncol 2008 May; 109(2): 182–6

    Article  PubMed  CAS  Google Scholar 

  35. Vansteenkiste J, Van Cutsem E, Dumez H, et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs 2008 Oct; 26(5): 483–8

    Article  PubMed  CAS  Google Scholar 

  36. Blumenschein Jr GR, Kies MS, Papadimitrakopoulou VA, et al. Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 2008 Feb; 26(1): 81–7

    Article  PubMed  CAS  Google Scholar 

  37. Kelly WK, O’Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005 Jun 10; 23(17): 3923–31

    Article  PubMed  CAS  Google Scholar 

  38. Steele NL, Plumb JA, Vidal L, et al. A phase 1 pharmaco-kinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res 2008 Feb 1; 14(3): 804–10

    Article  PubMed  CAS  Google Scholar 

  39. De Bono JS, Kristeleit R, Tolcher A, et al. Phase I pharma-cokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res 2008 Oct 15; 14(20): 6663–73

    Article  PubMed  CAS  Google Scholar 

  40. Giles F, Fischer T, Cortes J, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006 Aug 1; 12(15): 4628–35

    Article  PubMed  CAS  Google Scholar 

  41. Viviani S, Bonfante V, Fasola C, et al. Phase II study of the histone-deacetylase inhibitor ITF2357 in relapsed/refractory Hodgkin’s lymphoma patients [abstract no. 0.8532]. 2008 Annual Meeting Proceedings of the American Society of Clinical Oncology (ASCO); 2008 May 30–Jun 3; Chicago (IL)

  42. Prince HM, Bishton M, Harrison S. The potential of histone deacetylase inhibitors for the treatment of multiple myeloma. Leuk Lymphoma 2008 Mar; 49(3): 385–7

    Article  PubMed  CAS  Google Scholar 

  43. Shah MH, Binkley P, Chan K, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006 Jul 1; 12(13): 3997–4003

    Article  PubMed  CAS  Google Scholar 

  44. Fouladi M, Furman WL, Chin T, et al. Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children’s Oncology Group report. J Clin Oncol 2006 Aug 1; 24(22): 3678–85

    Article  PubMed  CAS  Google Scholar 

  45. Schrump DS, Fischette MR, Nguyen DM, et al. Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res 2008 Jan 1; 14(1): 188–98

    Article  PubMed  CAS  Google Scholar 

  46. Patnaik A, Rowinsky EK, Villalona MA, et al. A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. Clin Cancer Res 2002 Jul; 8(7): 2142–8

    PubMed  CAS  Google Scholar 

  47. Reid T, Valone F, Lipera W, et al. Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer 2004 Sep; 45(3): 381–6

    Article  PubMed  Google Scholar 

  48. Carducci MA, Gilbert J, Bowling MK, et al. A phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res 2001 Oct; 7(10): 3047–55

    PubMed  CAS  Google Scholar 

  49. Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 2001 Aug; 7(8): 2292–300

    PubMed  CAS  Google Scholar 

  50. Phuphanich S, Baker SD, Grossman SA, et al. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study. Neuro Oncol 2005 Apr; 7(2): 177–82

    Article  PubMed  CAS  Google Scholar 

  51. Camacho LH, Olson J, Tong WP, et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Invest New Drugs 2007 Apr; 25(2): 131–8

    Article  PubMed  CAS  Google Scholar 

  52. Atmaca A, Al-Batran SE, Maurer A, et al. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 2007 Jul 16; 97(2): 177–82

    Article  PubMed  CAS  Google Scholar 

  53. Kummar S, Gutierrez M, Gardner ER, et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 2007 Sep 15; 13 (18 Pt 1): 5411–7

    Article  PubMed  CAS  Google Scholar 

  54. Gore L, Rothenberg ML, O’Bryant CL, et al. 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 2008 Jul 15; 14(14): 4517–25

    Article  PubMed  CAS  Google Scholar 

  55. Prakash S, Foster BJ, Meyer M, et al. Chronic oral administration of CI-994: a phase 1 study. Invest New Drugs 2001; 19(1): 1–11

    Article  PubMed  CAS  Google Scholar 

  56. Siu LL, Pili R, Duran I, et al. Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol 2008 Apr 20; 26(12): 1940–7

    Article  PubMed  CAS  Google Scholar 

  57. Garcia-Manero G, Assouline S, Cortes J, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008 Aug 15; 112(4): 981–9

    Article  PubMed  CAS  Google Scholar 

  58. Insinga A, Monestiroli S, Ronzoni S, et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nature Med 2005 Jan; 11(1): 71–6

    Article  PubMed  CAS  Google Scholar 

  59. Edwards A, Li J, Atadja P, et al. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells. Mol Cancer Ther 2007 Sep; 6(9): 2515–24

    Article  PubMed  CAS  Google Scholar 

  60. Xu W, Ngo L, Perez G, et al. Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor. Proc Natl Acad Sci U S A 2006 Oct 17; 103(42): 15540–5

    Article  PubMed  CAS  Google Scholar 

  61. Inoue S, Riley J, Gant TW, et al. Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 2007 Aug; 21(8): 1773–82

    Article  PubMed  CAS  Google Scholar 

  62. Rosato RR, Maggio SC, Almenara JA, et al. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol Pharmacol 2006 Jan; 69(1): 216–25

    PubMed  CAS  Google Scholar 

  63. Butler LM, Zhou X, Xu WS, et al. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci U S A 2002 Sep 3; 99(18): 11700–5

    Article  PubMed  CAS  Google Scholar 

  64. Chen G, Li A, Zhao M, et al. Proteomic analysis identifies protein targets responsible for depsipeptide sensitivity in tumor cells. J Proteome Res 2008 Jul; 7(7): 2733–42

    Article  PubMed  CAS  Google Scholar 

  65. Noh EJ, Lee JS. Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2-M transition. Biochem Biophys Res Commun 2003 Oct 17; 310(2): 267–73

    Article  PubMed  CAS  Google Scholar 

  66. Qian X, Ara G, Mills E, et al. Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer 2008 Mar 15; 122(6): 1400–10

    Article  PubMed  CAS  Google Scholar 

  67. Cheng YC, Lin H, Huang MJ, et al. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res 2007 Oct; 31(10): 1403–11

    Article  PubMed  CAS  Google Scholar 

  68. Komatsu N, Kawamata N, Takeuchi S, et al. SAHA, a HDAC inhibitor, has profound anti-growth activity against non-small cell lung cancer cells. Oncol Rep 2006 Jan; 15(1): 187–91

    PubMed  CAS  Google Scholar 

  69. Valentini A, Gravina P, Federici G, et al. Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol Ther 2007 Feb; 6(2): 185–91

    Article  PubMed  CAS  Google Scholar 

  70. Sakajiri S, Kumagai T, Kawamata N, et al. Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines. Exp Hematol 2005 Jan; 33(1): 53–61

    Article  PubMed  CAS  Google Scholar 

  71. Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A 2004 Feb 3; 101(5): 1241–6

    Article  PubMed  CAS  Google Scholar 

  72. Alao JP, Stavropoulou AV, Lam EW, et al. Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells. Mol Cancer 2006; 5: 8

    Article  PubMed  CAS  Google Scholar 

  73. Qian DZ, Kato Y, Shabbeer S, et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006 Jan 15; 12(2): 634–42

    Article  PubMed  CAS  Google Scholar 

  74. Kim MS, Kwon HJ, Lee YM, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nature Med 2001 Apr; 7(4): 437–43

    Article  PubMed  Google Scholar 

  75. Kang JH, Kim MJ, Chang SY, et al. CCAAT box is required for the induction of human thrombospondin-1 gene by trichostatin A. J Cell Biochem 2008 Jul 1; 104(4): 1192–203

    Article  PubMed  CAS  Google Scholar 

  76. Kwon HJ, Kim MS, Kim MJ, et al. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002 Jan 20; 97(3): 290–6

    Article  PubMed  CAS  Google Scholar 

  77. Mie Lee Y, Kim SH, Kim HS, et al. Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1 alpha activity. Biochem Biophys Res Commun 2003 Jan 3; 300(1): 241–6

    Article  PubMed  Google Scholar 

  78. Chinnaiyan P, Varambally S, Tomlins SA, et al. Enhancing the antitumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition. Int J Cancer 2006 Feb 15; 118(4): 1041–50

    Article  PubMed  CAS  Google Scholar 

  79. Sasakawa Y, Naoe Y, Noto T, et al. Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. Biochem Pharmacol 2003 Sep 15; 66(6): 897–906

    Article  PubMed  CAS  Google Scholar 

  80. Zgouras D, Becker U, Loitsch S, et al. Modulation of angiogenesis-related protein synthesis by valproic acid. Biochem Biophys Res Commun 2004 Apr 9; 316(3): 693–7

    Article  PubMed  CAS  Google Scholar 

  81. Deroanne CF, Bonjean K, Servotte S, et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002 Jan 17; 21(3): 427–36

    Article  PubMed  CAS  Google Scholar 

  82. Joseph J, Mudduluru G, Antony S, et al. Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB. Oncogene 2004 Aug 19; 23(37): 6304–15

    Article  PubMed  CAS  Google Scholar 

  83. Mazieres J, Tovar D, He B, et al. Epigenetic regulation of RhoB loss of expression in lung cancer. BMC Cancer 2007; 7: 220

    Article  PubMed  CAS  Google Scholar 

  84. Liu LT, Chang HC, Chiang LC, et al. Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res 2003 Jun 15; 63(12): 3069–72

    PubMed  CAS  Google Scholar 

  85. Xu WS, Perez G, Ngo L, et al. Induction of polyploidy by histone deacetylase inhibitor: a pathway for antitumor effects. Cancer Research 2005 Sep 1; 65(17): 7832–9

    PubMed  CAS  Google Scholar 

  86. Stevens FE, Beamish H, Warrener R, et al. Histone deacetylase inhibitors induce mitotic slippage. Oncogene 2008 Feb 28; 27(10): 1345–54

    Article  PubMed  CAS  Google Scholar 

  87. Magnaghi-Jaulin L, Eot-Houllier G, Fulcrand G, et al. Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint. Cancer Res 2007 Jul 1; 67(13): 6360–7

    Article  PubMed  CAS  Google Scholar 

  88. Chen CL, Sung J, Cohen M, et al. Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther 2006 Nov; 319(2): 533–42

    Article  PubMed  CAS  Google Scholar 

  89. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 2003 Aug 1; 63(15): 4460–71

    PubMed  CAS  Google Scholar 

  90. Domingo-Domenech J, Pippa R, Tapia M, et al. Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat 2008 Nov; 112(1): 53–62

    Article  PubMed  CAS  Google Scholar 

  91. Dai Y, Rahmani M, Dent P, et al. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 2005 Jul; 25(13): 5429–44

    Article  PubMed  CAS  Google Scholar 

  92. Inoue S, Walewska R, Dyer MJ, et al. Downregulation of Mcl-1 potentiates HDAC inhibitors-mediated apoptosis in leukemic cells. Leukemia 2008 Apr; 22(4): 819–25

    Article  PubMed  CAS  Google Scholar 

  93. Yeow WS, Ziauddin MF, Maxhimer JB, et al. Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01. Br J Cancer 2006 May 22; 94(10): 1436–45

    Article  PubMed  CAS  Google Scholar 

  94. Ungerstedt JS, Sowa Y, Xu WS, et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci U S A 2005 Jan 18; 102(3): 673–8

    Article  PubMed  CAS  Google Scholar 

  95. Fotheringham S, Epping MT, Stimson L, et al. Genomewide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 2009 Jan 6; 15(1): 57–66

    Article  PubMed  CAS  Google Scholar 

  96. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 2004 Jun 1; 10(11): 3839–52

    Article  PubMed  CAS  Google Scholar 

  97. Heider U, von Metzler I, Kaiser M, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol 2008 Feb; 80(2): 133–42

    Article  PubMed  CAS  Google Scholar 

  98. Miller CP, Ban K, Dujka ME, et al. NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 2007 Jul 1; 110(1): 267–77

    Article  PubMed  CAS  Google Scholar 

  99. Dai Y, Chen S, Kramer LB, et al. Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 2008 Jan 15; 14(2): 549–58

    Article  PubMed  CAS  Google Scholar 

  100. Miller CP, Rudra S, Keating MJ, et al. Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells. Blood 2009 Apr 30; 113(18): 4289–99

    Article  PubMed  CAS  Google Scholar 

  101. Emanuele S, Lauricella M, Carlisi D, et al. SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis 2007 Jul; 12(7): 1327–38

    Article  PubMed  CAS  Google Scholar 

  102. Pitts TM, Morrow M, Kaufman SA, et al. Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther 2009 Feb; 8(2): 342–9

    Article  PubMed  CAS  Google Scholar 

  103. Lin Z, Bazzaro M, Wang MC, et al. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res 2009 Jan 15; 15(2): 570–7

    Article  PubMed  CAS  Google Scholar 

  104. Nawrocki ST, Carew JS, Pino MS, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006 Apr 1; 66(7): 3773–81

    Article  PubMed  CAS  Google Scholar 

  105. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006 Nov 15; 108(10): 3441–9

    Article  PubMed  CAS  Google Scholar 

  106. Nawrocki ST, Carew JS, Maclean KH, et al. Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood 2008 Oct 1; 112(7): 2917–26

    Article  PubMed  CAS  Google Scholar 

  107. Badros AZ, Philip S, Niesvizk R, et al. Phase I trial of vorinostat plus bortezomib (bort) in relapsed/refractory multiple myeloma (mm) patients (pts) [abstract no. 8548]. 2008 Annual Meeting Proceedings of the American Society of Clinical Oncology (ASCO); 2008 May 30—Jun 3; Chicago (IL)

  108. Petrella A, D’Acunto CW, Rodriquez M, et al. Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1. Eur J Cancer 2008 Mar; 44(5): 740–9

    Article  PubMed  CAS  Google Scholar 

  109. Liu T, Kuljaca S, Tee A, et al. Histone deacetylase inhibitors: multifunctional anticancer agents. Cancer Treat Rev 2006 May; 32(3): 157–65

    Article  PubMed  CAS  Google Scholar 

  110. Shabbeer S, Kortenhorst MS, Kachhap S, et al. Multiple Molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo. Prostate 2007 Jul 1; 67(10): 1099–110

    Article  PubMed  CAS  Google Scholar 

  111. Jiang K, Sun J, Cheng J, et al. Akt mediates Ras down-regulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 2004 Jun; 24(12): 5565–76

    Article  PubMed  CAS  Google Scholar 

  112. Sawada K, Mitra AK, Radjabi AR, et al. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res 2008 Apr 1; 68(7): 2329–39

    Article  PubMed  CAS  Google Scholar 

  113. Juan LJ, Shia WJ, Chen MH, et al. Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 2000 Jul 7; 275(27): 20436–43

    Article  PubMed  CAS  Google Scholar 

  114. Luo J, Su F, Chen D, et al. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000 Nov 16; 408(6810): 377–81

    Article  PubMed  CAS  Google Scholar 

  115. Martinez-Balbas MA, Bauer UM, Nielsen SJ, et al. Regulation of E2F1 activity by acetylation. EMBO J 2000 Feb 15; 19(4): 662–71

    Article  PubMed  CAS  Google Scholar 

  116. Kovacs JJ, Murphy PJ, Gaillard S, et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005 May 27; 18(5): 601–7

    Article  PubMed  CAS  Google Scholar 

  117. Jeong J, Juhn K, Lee H, et al. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med 2007 Feb 28; 39(1): 8–13

    PubMed  CAS  Google Scholar 

  118. Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature 2002 May 23; 417(6887): 455–8

    Article  PubMed  CAS  Google Scholar 

  119. Li Y, Zhang X, Polakiewicz RD, et al. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem 2008 May 9; 283(19): 12686–90

    Article  PubMed  CAS  Google Scholar 

  120. Ito A, Kawaguchi Y, Lai CH, et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 2002 Nov 15; 21(22): 6236–45

    Article  PubMed  CAS  Google Scholar 

  121. Roy S, Tenniswood M. Site-specific acetylation of p53 directs selective transcription complex assembly. J Biol Chem 2007 Feb 16; 282(7): 4765–71

    Article  PubMed  CAS  Google Scholar 

  122. Lu Z, Luo RZ, Peng H, et al. E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer. Oncogene 2006 Jan 12; 25(2): 230–9

    Article  PubMed  CAS  Google Scholar 

  123. Lu Z, Luo RZ, Peng H, et al. Transcriptional and post-transcriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Clin Cancer Res 2006 Apr 15; 12(8): 2404–13

    Article  PubMed  CAS  Google Scholar 

  124. Feng W, Lu Z, Luo RZ, et al. Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. Int J Cancer 2007 Apr 15; 120(8): 1664–8

    Article  PubMed  CAS  Google Scholar 

  125. Chen CS, Wang YC, Yang HC, et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res 2007 Jun 1; 67(11): 5318–27

    Article  PubMed  CAS  Google Scholar 

  126. Haggarty SJ, Koeller KM, Wong JC, et al. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 2003 Apr 15; 100(8): 4389–94

    Article  PubMed  CAS  Google Scholar 

  127. Wang Y, Wang SY, Zhang XH, et al. FK228 inhibits Hsp90 chaperone function in K562 cells via hyper-acetylation of Hsp70. Biochem Biophys Res Commun 2007 May 18; 356(4): 998–1003

    Article  PubMed  CAS  Google Scholar 

  128. Sawada M, Sun W, Hayes P, et al. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 2003 Apr; 5(4): 320–9

    Article  PubMed  CAS  Google Scholar 

  129. Subramanian C, Opipari Jr AW, Bian X, et al. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 2005 Mar 29; 102(13): 4842–7

    Article  PubMed  CAS  Google Scholar 

  130. Shan B, Yao TP, Nguyen HT, et al. Requirement of HDAC6 for transforming growth factor-ta1-induced epithelial-mesenchymal transition. J Biol Chem 2008 Jul 25; 283(30): 21065–73

    Article  PubMed  CAS  Google Scholar 

  131. Munster P, Marchion D, Bicaku E, et al. Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J Clin Oncol 2007 May 20; 25(15): 1979–85

    Article  PubMed  CAS  Google Scholar 

  132. Candelaria M, Gallardo-Rincon D, Arce C, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 2007 Sep; 18(9): 1529–38

    Article  PubMed  CAS  Google Scholar 

  133. Braiteh F, Soriano AO, Garcia-Manero G, et al. Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res 2008 Oct 1; 14(19): 6296–301

    Article  PubMed  CAS  Google Scholar 

  134. Ramalingam SS, Parise RA, Ramanathan RK, et al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007 Jun 15; 13(12): 3605–10

    Article  PubMed  CAS  Google Scholar 

  135. Pauer LR, Olivares J, Cunningham C, et al. Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest 2004; 22(6): 886–96

    Article  PubMed  CAS  Google Scholar 

  136. Sung MW, Waxman S. Combination of cytotoxic-differentiation therapy with 5-fluorouracil and phenyl-butyrate in patients with advanced colorectal cancer. Anticancer Res 2007 Mar–Apr; 27(2): 995–1001

    PubMed  CAS  Google Scholar 

  137. Undevia SD, Kindler HL, Janisch L, et al. A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine. Ann Oncol 2004 Nov; 15(11): 1705–11

    Article  PubMed  CAS  Google Scholar 

  138. Richards DA, Boehm KA, Waterhouse DM, et al. Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study. Ann Oncol 2006 Jul; 17(7): 1096–102

    Article  PubMed  CAS  Google Scholar 

  139. Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in meta-static breast cancer: a California Cancer Consortium study. Clin Cancer Res 2008 Nov 1; 14(21): 7138–42

    Article  PubMed  CAS  Google Scholar 

  140. Woyach JA, Kloos RT, Ringel MD, et al. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab 2009 Jan; 94(1): 164–70

    Article  PubMed  CAS  Google Scholar 

  141. Galanis E, Jaeckle KA, Maurer MJ, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 2009 Apr 20; 27(12): 2052–8

    Article  PubMed  CAS  Google Scholar 

  142. Ramalingam SS, Belani CP, Ruel C, et al. Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural meso-thelioma. J Thorac Oncol 2009 Jan; 4(1): 97–101

    Article  PubMed  Google Scholar 

  143. Woo S, Gardner ER, Chen X, et al. Population pharma-cokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res 2009 Feb 15; 15(4): 1496–503

    Article  PubMed  CAS  Google Scholar 

  144. Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 2005 Dec; 84 Suppl. 1: 61–6

    Article  PubMed  CAS  Google Scholar 

  145. Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 2007 Apr 1; 109(7): 2781–90

    PubMed  CAS  Google Scholar 

  146. Ryan QC, Headlee D, Acharya M, 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 Jun 10; 23(17): 3912–22

    Article  PubMed  CAS  Google Scholar 

  147. Hauschild A, Trefzer U, Garbe C, et al. Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-4-[(2-aminophenyl)-carbamoyl]-benzyl-carbamate in pretreated metastatic melanoma. Melanoma Res 2008 Aug; 18(4): 274–8

    Article  PubMed  CAS  Google Scholar 

  148. Marchion DC, Bicaku E, Turner JG, et al. Synergistic interaction between histone deacetylase and topoisomerase II inhibitors is mediated through topoisomerase IIbeta. Clin Cancer Res 2005 Dec 1; 11(23): 8467–75

    Article  PubMed  CAS  Google Scholar 

  149. Marchion DC, Bicaku E, Daud AI, et al. In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 2005 Dec; 4(12): 1993–2000

    Article  PubMed  CAS  Google Scholar 

  150. Kaminskas E, Farrell AT, Wang YC, et al. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 2005 Mar; 10(3): 176–82

    Article  PubMed  CAS  Google Scholar 

  151. Dowdy SC, Jiang S, Zhou XC, et al. Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Mol Cancer Ther 2006 Nov; 5(11): 2767–76

    Article  PubMed  CAS  Google Scholar 

  152. Catalano MG, Poli R, Pugliese M, et al. Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines. Endocr Relat Cancer 2007 Sep; 14(3): 839–45

    Article  PubMed  CAS  Google Scholar 

  153. Lee JH, Park JH, Jung Y, et al. Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells. Mol Cancer Ther 2006 Dec; 5(12): 3085–95

    Article  PubMed  CAS  Google Scholar 

  154. Gao N, Rahmani M, Shi X, et al. Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress. Blood 2006 Jan 1; 107(1): 241–9

    Article  PubMed  CAS  Google Scholar 

  155. Zhao Y, Tan J, Zhuang L, et al. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci U S A 2005 Nov 1; 102(44): 16090–5

    Article  PubMed  CAS  Google Scholar 

  156. Cameron EE, Bachman KE, Myohanen S, et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999 Jan; 21(1): 103–7

    Article  PubMed  CAS  Google Scholar 

  157. Shiozawa K, Nakanishi T, Tan M, et al. Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Clin Cancer Res 2009 Mar 1; 15(5): 1698–707

    Article  PubMed  CAS  Google Scholar 

  158. Rubin EH, Agrawal NG, Friedman EJ, et al. A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res 2006 Dec 1; 12(23): 7039–45

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Gonda 19-460, Rochester, Minnesota, 55905, USA

    Xujun Ma, Hany H. Ezzeldin &  Robert B. Diasio

Authors
  1. Xujun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hany H. Ezzeldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert B. Diasio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert B. Diasio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, X., Ezzeldin, H.H. & Diasio, R.B. Histone Deacetylase Inhibitors. Drugs 69, 1911–1934 (2009). https://doi.org/10.2165/11315680-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11315680-000000000-00000

Keywords

Search

Navigation