The Use of Histone Deacetylase Inhibitors for the Treatment of Solid Tumors

US Oncological Disease, 2007;1(2):12-6 DOI:
Citation US Oncological Disease, 2007;1(2):12-6 DOI:

‘Epigenetics’ is a term used to describe heritable states of gene expression that are not due to changes in DNA sequence. Epigenetic phenomena have been shown to play an important role in carcinogenesis and tumor progression. Such phenomena also represent potential therapeutic targets for cancer treatment as they are potentially reversible. Two such phenomena are epigenetic changes in DNA methylation, resulting in altered genetic expression, and histone modifications.1 This article focuses on histone modifications and thebalance of acetylation/deacetylation in tumor cells as a therapeutic target for anticancer therapies.

DNA wraps around a core of eight histone proteins (pairs of H2A, H2B, H3, and H4) to form nucleosomes. Lysine residues on histones are a target of acetylation, via histone acetyltransferases (HATs), and deacetylation, via histone deacetylases (HDACs). Acetylation neutralizes the positive charge of the lysine ε-amino group of the core histone tail. Put simply, this results in an ‘unwrapped’ DNA conformation, allowing access to DNA by transcription factors and co-activators. Deacetylation of lysine residues leads to tighter packaging of DNA and silencing of transcription.1

Mutations in HATs and recruitment of HDACs have both been associated with transcriptional repression of genes, resulting in cell growth and neoplastic transformation.2 These enzymes also have non-histone substrates, including transcription factors and other proteins, and the balance of acetylation/deacetylation can influence protein stability, protein localization, binding of transcription factors to DNA, and apoptosis. There are four classes of HDAC, with class I, II, and IV HDACs possessing a catalytic domain with a zinc pocket, which is important for the binding of HDAC inhibitors (HDACi). Zinc-independent and nicotinamide adenine dinucleotide (NAD)-dependent class III HDACs are not affected by the HDACi currently in clinical development. Class I HDACs are found mainly in the nucleus, while class II HDACs (4, 5, 6, 7, 9, and 10) are seen in both the nucleus and the cytoplasm.3,4 The class IV family consists of HDAC11, which shares features of both class I and class II enzymes.4 Several classes of HDACi have been identified (see Table 1):5,6
  • short-chain fatty acids, such as phenylbutyrates;7
  • hydroxamic acids, including trichostatin A (TSA);8
  • vorinostat (suberoylanilide hydroxamic acid (SAHA)),9 oxamflatin, belinostat (PXD101), LAQ824, and LBH589;
  • cyclic tetrapeptides containing a 2-amino-8-oxo-9, 10-epoxy-decanoyl (AOE) moiety, trapoxin A;10
  • cyclic peptides not containing the AOE moiety, romidepsin (depsipeptide, FK228), and apicidin;11 and
  • benzamides, including MS-275 (SNDX-275) and MGCD0103.12
This article focuses on HDACi in the treatment of solid tumors. Since the only US Food and Drug Administration (FDA)-approved HDACi to date is vorinostat, which was approved for use in cutaneous T-cell lymphoma (CTCL),the data leading to its approval are also presented here. Otherwise, the focus is on research in solid tumors; information on trials examining HDACi in hematological malignancies, including lymphoma, is not included. This article is not designed to discuss each HDACi in detail, but to present an overview of the available clinical data on HDACi, focusing on phase II trials.

Phase II Data for Single-agent Histone Deacetylase Inhibitors


To date, vorinostat is the only HDACi approved by the FDA for the treatment of malignancy. It is an orally active and potent inhibitor of HDAC activity,inhibiting both class I (HDAC1, HDAC2, HDAC3) and class II (HDAC 6) HDACs at nanomolar concentrations. It was approved in October 2006 for the treatment of cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease, or following two systemic therapies ( This approval was based on the results of two open-label clinical trials. The pivotal study supporting FDA approval was an open-label trial that enrolled 74 patients with stage IB–IVA CTCL who had received at least two prior systemic therapies. Patients were treated with 400mg oral vorinostat daily until disease progression or intolerable toxicity resulted. The primary end-point of the study was objective response rate (ORR), with secondary end-points of time to response (TTR), time to progression (TTP), duration of response (DOR), and relief of pruritis. ORR was 29.7%, with median DOR not reached but estimated to be ≥185 days; median TTP was 4.9 months, and 32% of patients reported relief of pruritis. The most common drug-related adverse events were diarrhea, fatigue, nausea, and anorexia, but ≥grade 3 events included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%).13

  1. Yoo CB, Jones PA, Epigenetic therapy of cancer: past, present, and future, Nat Reviews Drug Discov, 2006;5:37–50.
  2. Marks PA, Rifkind RA, Richon VM, et al., Histone deacetylases and cancer: causes and therapies, Nat Rev Cancer, 2001;1:194–202.
  3. Conley BA, Wright JJ, Kummar S, Targeting epigenetic abnormalities with histone deacetylase inhibitors, Cancer, 2006;107:832–40.
  4. Mehnert JM, Kelly WK, Histone deacetylase inhibitors: biology and mechanism of action, Cancer J, 2007;13:23–9.
  5. Bolden JE, Peart MJ, Johnstone RW, Anticancer activities of histone deacetylase inhibitors, Nat Rev Drug Discov, 2006;5:769–84.
  6. Kouzarides T, Histone acetylase and deacetylase in cell proliferation, Curr Opin Genet Dev, 1999;9:40–48.
  7. Newmark HL, Lupton JR, Young CW, Butyrate as a differentiating agent: pharmacokinetics, analogues and current status, Cancer Lett, 1994;78:1–5.
  8. Hoshikawa Y, Kwon HJ, Yoshida M, et al., Trichostatin A induces morphologic changes and gelsolin expression by inhibiting histone deacetylase in human carcinoma cell lines, Exp Cell Res, 1994;214: 189–97.
  9. Richon VM, Emiliani S, Verdin E, et al., A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases, Proc Natl Acad Sci U S A, 1998;95:3003–7.
  10. Kijima M, Yoshida M, Sugita K, et al., Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase, J Biol Chem, 1993;268:22429–35.
  11. Nakajima H, Kim YB, Terano H, et al., FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor, Exp Cell Res, 1998;241:126–33.
  12. Saito A, Yamashita T, Mariko Y, et al., A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors, Proc Natl Acad Sci U S A, 1999;96: 4592–7.
  13. Olsen EA, Kim YH, Kuzel TM, et al., Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma, J Clin Oncol, 2007;25: 3109–15.
  14. 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;109:31–9.
  15. Luu TH, Leong L, Morgan R, et al., Vorinostat (suberoylanilide hydroxamic acid) as salvage therapy in metastatic breast cancer (MBC): a California Cancer Consortium phase II study, 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S):11502.
  16. Galanis E, Jaeckle KA, Maurer MJ, et al., N047B: NCCTG phase II trial of vorinostat (suberoylanilide hydroxamic acid) in recurrent glioblastoma multiforme (GBM), 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S):2004.
  17. Hussain M, Dunn R, Rathkopf D, et al., Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): a phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862), 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S):5132.
  18. Traynor AM, Dubey S, Eickhoff J, et al., A phase II study of vorinostat (NSC 701852) in patients (pts) with relapsed non-small cell lung cancer (NSCLC), 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S):18044.
  19. Krug LM, Curley T, Schwartz L, et al., Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid, Clin Lung Cancer, 2006;7: 257–61.
  20. Parker C, Molife R, Karavasilis V, et al., Romidepsin (FK228), a histone deacetylase inhibitor: final results of a phase II study in metastatic hormone refractory prostate cancer (HRPC), 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S): 15507.
  21. Haigentz M, Kim M, Sarta C, et al., Clinical and translational studies of depsipeptide (romidepsin), a histone deacetylase (HDAC) inhibitor, in patients with squamous cell carcinoma of the head and neck (SCCHN): New York Cancer Consortium Trial P6335, 2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007;25(18S):6065.
  22. Shah MH, Binkley P, Chan K, et al., Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors, Clin Cancer Res, 2006;12:3997–4003.
  23. Wozniak A, O’Shaughnessy J, Fiorica J, Grove W, Phase II trial of CI-994 in patients (pts) with advanced nonsmall cell lung cancer (NSCLC), 1999 ASCO Annual Meeting Proceedings, J Clin Oncol,1999;abstract 1878.
  24. O’Shaughnessy J, Flaherty L, Fiorica J, Grove W, Phase II trial of CI-994 in patients (pts) with metastatic renal cell carcinoma (RCC), 1999 ASCO Annual Meeting Proceedings, J Clin Oncol, 1999; abstract 1346.
  25. Hauschild A, Trefzer U, Garbe C, et al., A phase II multicenter study on the histone deacetylase (HDAC) inhibitor MS-275, comparing two dosage schedules in metastatic melanoma, 2006 ASCO Annual Meeting Proceedings, J Clin Oncol, 2006;24(18S):8044.
  26. Reid T, Valone F, Lipera W, et al., Phase II trial of the histonedeacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer, Lung Cancer, 2004;45: 381–6.
  27. Yeo W, Lim R, Ma BB, et al., A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma,2007 ASCO Annual Meeting Proceedings, J Clin Oncol, 2007; 25(18S):15081.
  28. Munster P, Marchion D, Bicaku E, et al., Phase I trial of histone deacetylase inhibition by valproic acid followed by thetopoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study, J Clin Oncol, 2007;25(15): 1979–85.
  29. Nemunaitis JJ, Orr D, Eager R, et al., Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer, Cancer J, 2003;9:58–66.
  30. 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;17:1096–1102.
  31. 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;15:1705–11.
  32. 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;22:886–96.
  33. Chinnaiyan P, Vallabhaneni G, Armstrong E, et al., Modulation of radiation response by histone deacetylase inhibition, Int J RadiatOncol Biol Phys, 2005;62:223–9.
  34. Zhang Y, Jung M, Dritschilo A, Jung M, Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors, Radiat Res, 2004;161:667–74.
  35. Camphausen K, Cott T, Sproull M, Tofilon PJ, Enhancement of xenograft tumor radiosensitivity by the histone deactylase inhibitor MS-275 and correlation with histone hyperacetylation, Clin Cancer Res, 2004;10:6066–71.
  36. Conway RM, Madigan MC, Billson FA, Penfold PL, Vincristine- and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate, Eur J Cancer, 1998;34:1741–8.
  37. Kurz EU, Wilson SE, Leader KB, Sampey BP, et al., The histonedeacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines, Mol Cancer Ther, 2001;1:121–31.
  38. Donapaty S, Fuino L, Wittmann S, et al., Histone deacetylase inhibitor LAQ824 downregulates HER-2, induces growth arrest and apoptosis and sensitizes human breast cancer cells to herceptin and tubulin polymerizing agents, 2003 ASCO Annual Meeting Proceedings, J Clin Oncol, 2003;22:805.
  39. Niitsu N, Kasukabe T, Yokoyama A, et al., Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity, Mol Pharmacol, 2000;58:27–36.
  40. Zhu W-G, Lakshmanan RR, Beal MD, Otterson GA, DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors, Cancer Res, 2001;61:1327–33.
  41. Gore SD, Baylin S, Sugar E, et al., Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms, Cancer Res, 2006;66:6361–69.
  42. 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, Cancer Res, 2002;63: 3637–45.
  43. Chung EJ, Lee S, Sausville EA, et al., Histone deacetylase inhibitor pharmacodynamic analysis by multiparameter flow cytometry, Ann Clin Lab Sci, 2005;35:397–406.