HDAC Inhibitors and Cancer Therapy

  • Peter W. Atadja
Part of the Progress in Drug Research book series (PDR, volume 67)


Maintenance of normal cell growth and differentiation is highly dependent on coordinated and tight transcriptional regulation of genes. In cancer, genes encoding growth regulators are abnormally expressed. Particularly, silencing of tumor suppressor genes under the control of chromatin modifications is a major underlying cause of unregulated cellular proliferation and transformation. Thus mechanisms, which regulate chromatin structure and gene expression, have become attractive targets for anticancer therapy. Histone deacetylases are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. Research over the past decade has led to the development of histone deacetylase inhibitors as anticancer agents. In addition to their effect on chromatin and epigenetic mechanisms, HDAC inhibitors also modify the acetylation state of a large number of cellular proteins involved in oncogenic processes, resulting in antitumor effects. The current monograph will review the role of histone deacetylases in protumorigenic mechanisms and the current developmental status and prospects for their inhibitors in cancer therapy.


Multiple Myeloma Acute Myeloid Leukemia Acute Promyelocytic Leukemia HDAC Inhibitor Malignant Pleural Mesothelioma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I would like to thank Lei Jiang of the China Novartis Institute for Biomedical Research for assistance in drawing chemical structures and reviewing the chemistry sections.


  1. 1.
    Hager GL, McNally JG, Misteli T (2009) Transcription dynamics. Mol Cell 5:741–753CrossRefGoogle Scholar
  2. 2.
    Ellis L, Atadja PW, Johnstone RW (2009) Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 8:1409–1420PubMedCrossRefGoogle Scholar
  3. 3.
    Smith CL (2008) A shifting paradigm: histone deacetylases and transcriptional activation. Bioessays 30:15–24PubMedCrossRefGoogle Scholar
  4. 4.
    Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23PubMedCrossRefGoogle Scholar
  5. 5.
    Kim SC, Sprung R, Chen Y et al (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23:607–618PubMedCrossRefGoogle Scholar
  6. 6.
    Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedCrossRefGoogle Scholar
  7. 7.
    Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedCrossRefGoogle Scholar
  8. 8.
    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51PubMedCrossRefGoogle Scholar
  9. 9.
    Gao L, Cueto MA, Asselbergs F, Atadja P (2002) Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 277(28):25748–25755PubMedCrossRefGoogle Scholar
  10. 10.
    Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 33:17–31CrossRefGoogle Scholar
  11. 11.
    Spange S, Wagner T, Heinzel T, Krämer OH (2009) Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 41:185–198PubMedCrossRefGoogle Scholar
  12. 12.
    Smith KT, Workman JL (2009) Introducing the acetylome. Nat Biotechnol 27:917–919PubMedCrossRefGoogle Scholar
  13. 13.
    Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241PubMedCrossRefGoogle Scholar
  14. 14.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  15. 15.
    Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M (2004) Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5:455–463PubMedCrossRefGoogle Scholar
  16. 16.
    Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA 101:1241–1246PubMedCrossRefGoogle Scholar
  17. 17.
    Bhalla KN (2005) Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol 23:3971–3993PubMedCrossRefGoogle Scholar
  18. 18.
    Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP (1998) Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 90:1621–1625PubMedCrossRefGoogle Scholar
  19. 19.
    Wang Y, Wang SY, Zhang XH et al (2007) FK228 inhibits Hsp90 chaperone function in K562 cells via hyperacetylation of Hsp70. Biochem Biophys Res Commun 356:998–1003PubMedCrossRefGoogle Scholar
  20. 20.
    Bereshchenko OR, Gu W, Dalla-Favera R (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 32:606–613PubMedCrossRefGoogle Scholar
  21. 21.
    Li M, Luo J, Brooks CL, Gu W (2002) Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277:50607–50611PubMedCrossRefGoogle Scholar
  22. 22.
    Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606PubMedCrossRefGoogle Scholar
  23. 23.
    Luo J, Li M, Tang Y, Laszkowska M, Roeder RG, Gu W (2002) Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc Natl Acad Sci 101:2259–2264. Li M, Luo J, Brooks CL, Gu W. (2002) Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277:50607–50611PubMedCrossRefGoogle Scholar
  24. 24.
    Tang Y, Zhao W, Chen Y, Zhao Y, Gu W (2008) Acetylation is indispensable for p53 activation. Cell 133:612–626PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC (2000) Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101(1):79–89PubMedCrossRefGoogle Scholar
  26. 26.
    Lagger G, O’Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21(11):2672–2681PubMedCrossRefGoogle Scholar
  27. 27.
    Yu C, Subler M, Rahmani M et al (2003) Induction of apoptosis in BCR/ABL+ cells by histone deacetylase inhibitors involves reciprocal effects on the RAF/MEK/ERK and JNK pathways. Cancer Biol Ther 2:544–551PubMedGoogle Scholar
  28. 28.
    Nimmanapalli R, Fuino L, Bali P et al (2003) Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res 63:5126–5135PubMedGoogle Scholar
  29. 29.
    Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2:971–984PubMedGoogle Scholar
  30. 30.
    Guo F, Sigua C, Tao J, Bali P, George P, Li Y, Wittmann S, Moscinski L, Atadja P, Bhalla K (2004) Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res 64:2580–2589PubMedCrossRefGoogle Scholar
  31. 31.
    Nebbioso A, le Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P, Alvarez R, Schiavone EM, Ferrara F, Bresciani F, Weisz A, de Lera AR, Gronemeyer H, Altucci L (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 11:77–84PubMedCrossRefGoogle Scholar
  32. 32.
    Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A, Altucci L, Nervi C, Minucci S, Pelicci PG (2004) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11:71–76PubMedCrossRefGoogle Scholar
  33. 33.
    Hubbert C, Guardiola A, Shao R et al (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang X, Yuan Z, Zhang Y et al (2007) HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 27:197–213PubMedCrossRefGoogle Scholar
  35. 35.
    Tran AD, Marmo TP, Salam AA et al (2007) HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J Cell Sci 120:1469–1479PubMedCrossRefGoogle Scholar
  36. 36.
    Ellis L, Hammers H, Pili R (2009) Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 280:145–153PubMedCrossRefGoogle Scholar
  37. 37.
    Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634PubMedCrossRefGoogle Scholar
  38. 38.
    Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66:8814–8821PubMedCrossRefGoogle Scholar
  39. 39.
    Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T, Atadja P, Pili R (2008) Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 14(11):3589–3597PubMedCrossRefGoogle Scholar
  40. 40.
    Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401:188–193PubMedCrossRefGoogle Scholar
  41. 41.
    Boffa LC, Vidali G, Mann RS, Allfrey VG (1978) J Biol Chem. Suppression of histone deacetylation in vivo and in vitro by sodium butyrate 253:3364–3366Google Scholar
  42. 42.
    Gore SD, Carducci MA (2000) Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin Investig Drugs 9:2923–2934PubMedCrossRefGoogle Scholar
  43. 43.
    Santini V, Gozzini A, Scappini B, Grossi A, Rossi Ferrini P (2001) Searching for the magic bullet against cancer: the butyrate saga. Leuk Lymphoma 42:275–289PubMedCrossRefGoogle Scholar
  44. 44.
    Remiszewski SW (2003) The discovery of NVP-LAQ824: from concept to clinic. Curr Med Chem 10:2393–2402PubMedCrossRefGoogle Scholar
  45. 45.
    Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (1998) FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241:126–133PubMedCrossRefGoogle Scholar
  46. 46.
    Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 96:4592–4597PubMedCrossRefGoogle Scholar
  47. 47.
    Van Lint C, Emiliani S, Verdin E (1996) The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 5:245–253PubMedGoogle Scholar
  48. 48.
    Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK (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 2:151–163PubMedCrossRefGoogle Scholar
  49. 49.
    Boyes J, Byfield P, Nakatani Y, Ogryzko V (1998) Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594–598PubMedCrossRefGoogle Scholar
  50. 50.
    Waltzer L, Bienz M (1998) Drosophila CBP represses the transcription factor TCF to antagonize Wingless signalling. Nature 395:521–525PubMedCrossRefGoogle Scholar
  51. 51.
    Martínez-Balbás MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T (2000) Regulation of E2F1 activity by acetylation. EMBO J 19:662–671PubMedCrossRefGoogle Scholar
  52. 52.
    Marzio G, Wagener C, Gutierrez MI, Cartwright P, Helin K, Giacca M (2000) E2F family members are differentially regulated by reversible acetylation. J Biol Chem 275:10887–10892PubMedCrossRefGoogle Scholar
  53. 53.
    Piekarz RL, Robey R, Sandor V, Bakke S, Wilson WH, Dahmoush L, Kingma DM, Turner ML, Altemus R, Bates SE (2001) Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 98:2865–2868PubMedCrossRefGoogle Scholar
  54. 54.
    Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, Frankel SR (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31–39PubMedCrossRefGoogle Scholar
  55. 55.
    Ellis L, Pan Y, Smyth GK, George DJ, McCormack C, Williams-Truax R, Mita M, Beck J, Burris H, Ryan G, Atadja P, Butterfoss D, Dugan M, Culver K, Johnstone RW, Prince HM (2008) Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res 14:4500–4510PubMedCrossRefGoogle Scholar
  56. 56.
    Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12(10):1247–1252PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang C, Richon V, Ni X, Talpur R, Duvic M (2005) Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol 125:1045–1052PubMedCrossRefGoogle Scholar
  58. 58.
    Chen J, Fiskus W, Eaton K, Fernandez P, Wang Y, Rao R, Lee P, Joshi R, Yang Y, Kolhe R, Balusu R, Chappa P, Natarajan K, Jillella A, Atadja P, Bhalla KN (2009) Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism. Blood 113:4038–4048PubMedCrossRefGoogle Scholar
  59. 59.
    Fantin VR, Loboda A, Paweletz CP, Hendrickson RC, Pierce JW, Roth JA, Li L, Gooden F, Korenchuk S, Hou XS, Harrington EA, Randolph S, Reilly JF, Ware CM, Kadin ME, Frankel SR, Richon VM (2008) Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Cancer Res 68:3785–3794PubMedCrossRefGoogle Scholar
  60. 60.
    Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, Bhalla KN, Liu A, Parker K, Scott JW, Bishton M, Prince HM (2009) Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol 147:97–101PubMedCrossRefGoogle Scholar
  61. 61.
    Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla KA (2006) Phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635PubMedCrossRefGoogle Scholar
  62. 62.
    Otmann OG, Spencer A, Prince MH, Bhalla KN, Fischer T, Liu A, Parker K, Jalaluddin M, Laird G, Woo M, Scott JW, DeAngelo DJ (2008) Phase IA/II study of oral panobinostat (LBH589), a novel pan-deacetylase inhibitor (DACi) demonstrating efficacy in patients with advanced hematologic malignancies. American Society of Hematology annual conference 112, Abstract 958Google Scholar
  63. 63.
    Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM (2008) A phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111(3):1060–1066PubMedCrossRefGoogle Scholar
  64. 64.
    Bali P, George P, Cohen P, Tao J, Guo F, Sigua C, Vishvanath A, Scuto A, Annavarapu S, Fiskus W, Moscinski L, Atadja P, Bhalla K (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10:4991–4997PubMedCrossRefGoogle Scholar
  65. 65.
    Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN (2009) Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114:2733–2743PubMedCrossRefGoogle Scholar
  66. 66.
    San-Miguel JF, Sezer O, Siegel D, Guenther A, Mateos M-V, Blade J, Prosser I, Cavo M, Boccadoro M, Goebeler M, Bengoudifa BR, Hazell K, Klebsattel M, Bourquelot PM, Anderson KC (2009) A phase Ib, multicenter, open-label, dose-escalation study of oral panobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma. American Hematological Society meeting X, Abstract 3852Google Scholar
  67. 67.
    Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15:5250–5257PubMedCrossRefGoogle Scholar
  68. 68.
    Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 24:8567–8572CrossRefGoogle Scholar
  69. 69.
    Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738PubMedCrossRefGoogle Scholar
  70. 70.
    Krug LM, Curley T, Schwartz L, Richardson S, Marks P, Chiao J, Kelly WK (2006) Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clin Lung Cancer 7:257–261PubMedCrossRefGoogle Scholar
  71. 71.
    Carraway HE, Gore SD (2007) Addition of histone deacetylase inhibitors in combination therapy. J Clin Oncol 25(15):1955–1956PubMedCrossRefGoogle Scholar
  72. 72.
    Lee JH, Park JH, Jung Y, Kim JH, Jong HS, Kim TY, Bang YJ (2006) Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells. Mol Cancer Ther 5(12):3085–3095PubMedCrossRefGoogle Scholar
  73. 73.
    Ocker M, Alajati A, Ganslmayer M et al (2005) The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells. J Cancer Res Clin Oncol 131:385–394PubMedCrossRefGoogle Scholar
  74. 74.
    Maiso P, Carvajal-Vergara X, Ocio EM, López-Pérez R, Mateo G, Gutiérrez N, Atadja P, Pandiella A, San Miguel JF (2006) The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res 66(11):5781–5789PubMedCrossRefGoogle Scholar
  75. 75.
    Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T, Richon VM, Marks PA, Anderson KC (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101(10):4055–4062PubMedCrossRefGoogle Scholar
  76. 76.
    Ramalingam SS, Parise RA, Ramanathan RK, Lagattuta TF, Musguire LA, Stoller RG, Potter DM, Argiris AE, Zwiebel JA, Egorin MJ, Belani CP (2007) Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13:3605–3610PubMedCrossRefGoogle Scholar
  77. 77.
    Rathkpf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W, Scher HI (2010) A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 66:181–189Google Scholar
  78. 78.
    Capone M, Conte PF, Amadori D, Pronzato P, Wardley A, Dey H, Dzik-Jurasz A, Maclean N, McBride K, Fandi A (2009) Phase I trial of panobinostat (LBH589) in combination with trastuzumab in pretreated HER2-positive metastatic breast cancer: preliminary safety and tolerability results San Antonio Breast Cancer Symposium, Abstract #6101Google Scholar
  79. 79.
    Mehnert JM, Kelly WK (2007) Histone deacetylase inhibitors: biology and mechanism of action. Cancer J 13:23–29PubMedCrossRefGoogle Scholar

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© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Novartis Institute for Biomedical ResearchShanghaiChina

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