Medical Oncology

, 31:985 | Cite as

Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience

  • Pavel Bezecny
Review Article


Epigenetic mechanisms are increasingly recognized as a major factor contributing to pathogenesis of cancer including glioblastoma, the most common and most malignant primary brain tumour in adults. Enzymatic modifications of histone proteins regulating gene expression are being exploited for therapeutic drug targeting. Over the last decade, numerous studies have shown promising results with histone deacetylase (HDAC) inhibitors in various malignancies. This article provides a brief overview of mechanism of anti-cancer effect and pharmacology of HDAC inhibitors and summarizes results from pre-clinical and clinical studies in glioblastoma. It analyses experience with HDAC inhibitors as single agents as well as in combination with targeted agents, cytotoxic chemotherapy and radiotherapy. Hallmark features of glioblastoma, such as uncontrolled cellular proliferation, invasion, angiogenesis and resistance to apoptosis, have been shown to be targeted by HDAC inhibitors in experiments with glioblastoma cell lines. Vorinostat is the most advanced HDAC inhibitor that entered clinical trials in glioblastoma, showing activity in recurrent disease. Multiple phase II trials with vorinostat in combination with targeted agents, temozolomide and radiotherapy are currently recruiting. While the results from pre-clinical studies are encouraging, early clinical trials showed only modest benefit and the value of HDAC inhibitors for clinical practice will need to be confirmed in larger prospective trials. Further research in epigenetic mechanisms driving glioblastoma pathogenesis and identification of molecular subtypes of glioblastoma is needed. This will hopefully lead to better selection of patients who will benefit from treatment with HDAC inhibitors.


Histone deacetylase inhibitors Glioblastoma Vorinostat Romidepsin Valproic acid 



The author would like to thank Catherine Mitchell, MD (Royal Preston Hospital, UK) for her assistance with revising the manuscript.

Conflict of interest



  1. 1.
    Stupp R, Mason WP, Van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedGoogle Scholar
  2. 2.
    Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.PubMedGoogle Scholar
  3. 3.
    Kreisl TN, Lyndon K, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817–23.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31:3212–8.PubMedGoogle Scholar
  6. 6.
    Nagarajan RP, Costello JF. Epigenetic mechanisms in glioblastoma multiforme. Semin Cancer Biol. 2009;19:188–97.PubMedGoogle Scholar
  7. 7.
    Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.PubMedGoogle Scholar
  8. 8.
    Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76:75–100.PubMedGoogle Scholar
  9. 9.
    Wang Z, Zang C, Cui K, et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009;138:1019–31.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26:5541–52.PubMedGoogle Scholar
  11. 11.
    Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 2004;338:17–31.PubMedGoogle Scholar
  12. 12.
    Choudhary C, Kumar C, Gnad F, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834–40.PubMedGoogle Scholar
  13. 13.
    Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5:981–9.PubMedGoogle Scholar
  14. 14.
    DeRuijter AJM, van Gennip AH, Caron HN, Kemp S, van Kuilenburg ABP. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.Google Scholar
  15. 15.
    Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26:5420–32.PubMedGoogle Scholar
  16. 16.
    Peart MJ, Smyth GK, van Laar RK, et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2005;102:3697–702.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008;269:7–17.PubMedGoogle Scholar
  18. 18.
    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 USA. 2005;102:673–8.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Qian DZ, Wang X, Kachhap SK, et al. 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. 2004;64:6626–34.PubMedGoogle Scholar
  20. 20.
    Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci USA. 2012;109:6561–5.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Watanabe M, Adachi S, Matsubara H, et al. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int J Cancer. 2009;124:55–67.PubMedGoogle Scholar
  22. 22.
    Conti C, Leo E, Eichler GS, et al. Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res. 2010;70:4470–80.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Namdar M, Perez G, Ngo L, Marks PA. Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc Natl Acad Sci USA. 2010;107:20003–8.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Lee JH, Choy ML, Ngo L, Foster SS, Marks PA. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA. 2010;107:14639–44.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27:5459–68.PubMedGoogle Scholar
  26. 26.
    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.PubMedCentralPubMedGoogle Scholar
  27. 27.
    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.PubMedGoogle Scholar
  28. 28.
    Kelly WK, O’Connor OA, Krug ML, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23:3923–31.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Rubin EH, Agrawal NGB, 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;12:7039–45.PubMedGoogle Scholar
  30. 30.
    Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27:5410–7.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Whittaker SJ, Demierre M-F, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28:4485–91.PubMedGoogle Scholar
  32. 32.
    Sandor V, Bakke S, Robey RW, et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res. 2002;8:718–28.PubMedGoogle Scholar
  33. 33.
    Yin D, Ong JM, Hu J, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo. Clin Cancer Res. 2007;13:1045–52.PubMedGoogle Scholar
  34. 34.
    Xu J, Sampath D, Lang FF, et al. Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures. J Neurooncol. 2011;105:241–51.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Eyüpoglu IY, Hahnen E, Buslei R, et al. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. J Neurochem. 2005;93:992–9.PubMedGoogle Scholar
  36. 36.
    Ugur HC, Ramakrishna N, Bello L, et al. Continuous intracranial administration of suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth in an orthotopic glioma model. J Neurooncol. 2007;83:267–75.PubMedGoogle Scholar
  37. 37.
    Orzan F, Pellegatta S, Poliani PL, et al. Enhancer of zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol. 2011;37:381–94.PubMedGoogle Scholar
  38. 38.
    Xiao Y. Enhancer of zeste homolog 2: a potential target for tumor therapy. Int J Biochem Cell Biol. 2011;43:474–7.PubMedGoogle Scholar
  39. 39.
    Cao Q, Yu J, Dhanasekaran SM, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–84.PubMedCentralPubMedGoogle Scholar
  40. 40.
    An Z, Gluck CB, Choy ML, Kaufman LI. Suberoylanilide hydroxamic acid limits migration and invasion of glioma cells in two and three dimensional culture. Cancer Lett. 2010;292:215–27.PubMedGoogle Scholar
  41. 41.
    Svechnikova I, Almqvist PM, Ekström TJ. HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. Int J Oncol. 2008;32:821–7.PubMedGoogle Scholar
  42. 42.
    Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein. Cell. 1990;60:585–95.PubMedGoogle Scholar
  43. 43.
    Boulay J-L, Ionescu M-CS, Sivasankaran B, et al. The 10q 25.3–26.1G protein-coupled receptor gene GPR26 is epigenetically silenced in human gliomas. Int J Oncol. 2009;35:1123–31.PubMedGoogle Scholar
  44. 44.
    Vallejo I, Vallejo M. Pituitary adenylate cyclase-activating polypeptide induces astrocyte differentiation of precursor cells from developing cerebral cortex. Mol Cell Neurosci. 2002;21:671–83.PubMedGoogle Scholar
  45. 45.
    Clevers H. Wnt/beta-catenin signalling in development and disease. Cell. 2006;127:469–80.PubMedGoogle Scholar
  46. 46.
    Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98.PubMedGoogle Scholar
  47. 47.
    Foltz G, Yoon JG, Lee H, et al. Epigenetic regulation of wnt pathway antagonists in human glioblastoma multiforme. Genes Cancer. 2010;1:81–90.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Ai L, Tao Q, Zhong S, et al. Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis. 2006;27:1341–8.PubMedGoogle Scholar
  49. 49.
    Suzuki H, Toyota M, Carraway H, et al. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. Br J Cancer. 2008;98:1147–56.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Aguilera O, Fraga MF, Ballestar E, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25:4116–21.PubMedGoogle Scholar
  51. 51.
    He B, Reguart N, You L, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene. 2005;24:3054–8.PubMedGoogle Scholar
  52. 52.
    Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res. 1998;241:126–33.PubMedGoogle Scholar
  53. 53.
    Sandor V, Senderowicz A, Mertins S, et al. P21-dependent G1 arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer. 2000;83:817–25.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 2002;94:504–13.PubMedGoogle Scholar
  55. 55.
    Sawa H, Murakami H, Kumagai M, et al. Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo. Acta Neuropathol. 2004;107:523–31.PubMedGoogle Scholar
  56. 56.
    Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364.Google Scholar
  57. 57.
    Bradbury CA, Khanim FL, Hayden R, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that change selectively in response to deacetylase inhibitors. Leukemia. 2005;19:1751–9.PubMedGoogle Scholar
  58. 58.
    Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res. 2004;64:1079–86.PubMedGoogle Scholar
  59. 59.
    Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Duenas-Gonzales A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev. 2008;34:206–22.Google Scholar
  61. 61.
    Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, et al. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines. Cancer Cell Int. 2006;6:2.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Strey CW, Schamell L, Oppermann E, Haferkamp A, Bechstein WO, Blaheta RA. Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro. Exp Ther Med. 2011;2:301–7.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Xia Q, Sung J, Chowdhury W, et al. Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. Cancer Res. 2006;66:7237–44.PubMedGoogle Scholar
  64. 64.
    Papi A, Ferreri AM, Rocchi P, Guerra F, Orlandi M. Epigenetic modifiers as anticancer drugs: effectiveness of valproic acid in neural crest-derived tumor cells. Anticancer Res. 2010;30:535–40.PubMedGoogle Scholar
  65. 65.
    Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia. 2004;45:737–44.PubMedGoogle Scholar
  66. 66.
    Bobustuc GC, Baker CH, Limaye A, et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. 2010;12:917–27.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Eyüpoglu IY, Hahnen E, Tränkle C, et al. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Mol Cancer Ther. 2006;5:1248–55.PubMedGoogle Scholar
  68. 68.
    Simonini MV, Camargo LM, Dong E, et al. The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proc Natl Acad Sci USA. 2006;103:1587–92.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Sun P, Xia S, Lal B, et al. DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells. 2009;27:1473–86.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Asklund T, Appelskog IB, Ammerpohl O, Ekström TJ, Almqvist PM. Histone deacetylase inhibitor 4-phenylbutyrate modulates glial fibrillary acidic protein and connexin 43 expression, and enhances gap-junction communication, in human glioblastoma cells. Eur J Cancer. 2004;40:1073–81.PubMedGoogle Scholar
  71. 71.
    Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417:455–8.PubMedGoogle Scholar
  72. 72.
    Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5:769–84.PubMedGoogle Scholar
  73. 73.
    Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA. 2003;100:4389–94.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Aldana-Masangkay GI, Sakamoto KM. The role of HDAC6 in cancer. J Biomed Biotechnol. 2011;2011:875824.Google Scholar
  75. 75.
    Zhang X, Yuan Z, Zhang Y, et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell. 2007;27:197–213.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Wu Y, Song SW, Sun J, Bruner JM, Fuller GN, Zhang W. IIp45 inhibits cell migration through inhibition of HDAC6. J Biol Chem. 2010;285:3554–60.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.Google Scholar
  78. 78.
    Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.PubMedGoogle Scholar
  79. 79.
    Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21:2683–710.PubMedGoogle Scholar
  80. 80.
    Clark PA, Iida M, Treisman DM, et al. Activation of multiple ERBB family receptors mediates glioblastoma cancer stem-like cell resistance to EGFR-targeted inhibition. Neoplasia. 2012;14:420–8.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Nimmanapalli R, Fuino L, Bali P, et al. 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. 2003;63:5126–35.PubMedGoogle Scholar
  82. 82.
    Yu C, Dasmahapatra G, Dent P, Grant S. Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. Leukemia. 2005;19:1579–89.PubMedGoogle Scholar
  83. 83.
    Yu C, Friday BB, Lai JP, et al. Abrogation of MAPK and Akt signalling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin Cancer Res. 2007;13:1140–8.PubMedGoogle Scholar
  84. 84.
    Witta SE, Gemmill RM, Hirsch FR, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006;66:944–50.PubMedGoogle Scholar
  85. 85.
    Jane EP, Premkumar DR, Addo-Yobo SO, Pollack IF. Abrogation of mitogen-activated protein kinase and Akt signalling by vandetanib synergistically potentiates histone deacetylase inhibitor-induced apoptosis in human glioma cells. J Pharmacol Exp Ther. 2009;331:327–37.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Marino AM, Sofiadis A, Baryawno N, et al. Enhanced effects by 4-phenylbutyrate in combination with RTK inhibitors on proliferation in brain tumor cell models. Biochem Biophys Res Commun. 2011;411:208–12.PubMedGoogle Scholar
  87. 87.
    Bezecny P, Wong F, Sang NJPX, Pieri C, Mulholland PJ, Sheer D. Addition of erlotinib changes gene expression in glioblastoma cell lines treated with vorinostat. Eur J Cancer. 2011;47(Suppl 1):S578.Google Scholar
  88. 88.
    Lai CJ, Bao R, Tao X, et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 2010;70:3647–56.PubMedGoogle Scholar
  89. 89.
    Yin D, Zhou H, Kumagai T, et al. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene. 2005;24:344–54.PubMedGoogle Scholar
  90. 90.
    Laurent N, de Boüard S, Guillamo JS, et al. Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Mol Cancer Ther. 2004;3:129–36.PubMedGoogle Scholar
  91. 91.
    Yu C, Friday BB, Yang L, et al. Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. Neuro Oncol. 2008;10:309–19.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119:941–53.PubMedGoogle Scholar
  93. 93.
    Singh MM, Manton CA, Bhat KP, et al. Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol. 2011;13:894–903.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Dwarkanath BS, Zolzer F, Chandana S, et al. Heterogeneity in 2-deoxy-d-glucose-induced modifications in energetic and radiation responses of human tumor cell lines. Int J Radiat Oncol Biol Phys. 2001;50:1051–61.PubMedGoogle Scholar
  95. 95.
    Mohanti BK, Rath GK, Anantha N, et al. Improving cancer radiotherapy with 2-deoxy-d-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys. 1996;35:103–11.PubMedGoogle Scholar
  96. 96.
    Egler V, Korur S, Failly M, et al. Histone deacetylase inhibition and blockade of the glycolytic pathway synergistically induce glioblastoma cell death. Clin Cancer Res. 2008;14:3132–40.PubMedGoogle Scholar
  97. 97.
    Sarcar B, Kahali S, Chinnaiyan P. Vorinostat enhances the cytotoxic effects of the topoisomerase I inhibitor SN38 in glioblastoma cell lines. J Neurooncol. 2010;99:201–7.PubMedGoogle Scholar
  98. 98.
    Bevins RL, Zimmer SG. It’s about time: scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells. Cancer Res. 2005;65:6957–66.PubMedGoogle Scholar
  99. 99.
    Daud AI, Dawson J, DeConti RC, et al. Potentiation of a topoisomerase I inhibitor, karenitecin, by the histone deacetylase inhibitor valproic acid in melanoma: translational and phase I/II clinical trial. Clin Cancer Res. 2009;15:2479–87.PubMedGoogle Scholar
  100. 100.
    Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6:789–802.PubMedGoogle Scholar
  101. 101.
    Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res. 2003;63:7291–300.PubMedGoogle Scholar
  102. 102.
    Das CM, Aguilera D, Vasquez H, et al. Valproic acid induces p21 and topoisomerase-II (α/β) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol. 2007;85:159–70.PubMedGoogle Scholar
  103. 103.
    Ciusani E, Balzarotti M, Calatozzolo C, et al. Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines. Oncol Res. 2007;16:453–63.PubMedGoogle Scholar
  104. 104.
    Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN. Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem. 2004;92:223–37.PubMedGoogle Scholar
  105. 105.
    Marchion DC, Bicaku E, Turner JG, Daud AI, Sullivan DM, Munster PN. Synergistic interaction between histone deacetylase and topoisomerase II inhibitors is mediated through topoisomerase IIbeta. Clin Cancer Res. 2005;11:8467–75.PubMedGoogle Scholar
  106. 106.
    Bangert A, Häcker S, Cristofanon S, Debatin KM, Fulda S. Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275. Anticancer Drug. 2011;22:494–9.Google Scholar
  107. 107.
    Xiao JJ, Huang Y, Dai Z, et al. Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005;314:467–75.PubMedGoogle Scholar
  108. 108.
    Tabe Y, Konopleva M, Contractor R, et al. Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood. 2006;107:1546–54.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Kim YK, Kim NH, Hwang JW, et al. Histone deacetylase inhibitor apicidin-mediated drug resistance: involvement of P-glycoprotein. Biochem Biophys Res Commun. 2008;368:959–64.PubMedGoogle Scholar
  110. 110.
    Kim SN, Kim NH, Lee W, Seo DW, Kim YK. Histone deacetylase inhibitor induction of P-glycoprotein transcription requires both histone deacetylase 1 dissociation and recruitment of CAAT/enhancer binding protein beta and pCAF to the promoter region. Mol Cancer Res. 2009;7:735–44.PubMedGoogle Scholar
  111. 111.
    Munshi A, Tanaka T, Hobbs ML, Tucker SL, Richon VM, Meyn RE. Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther. 2006;5:1967–74.PubMedGoogle Scholar
  112. 112.
    Camphausen K, Tofilon PJ. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol. 2007;25:4051–6.PubMedGoogle Scholar
  113. 113.
    Camphausen K, Cerna D, Scott T, et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int J Cancer. 2005;114:380–6.PubMedGoogle Scholar
  114. 114.
    Chinnaiyan P, Vallabhaneni G, Armstrong E, Huang SM, Harari PM. Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys. 2005;62:223–9.PubMedGoogle Scholar
  115. 115.
    Zhang Y, Carr T, Dimtchev A, Zaer N, Dritschilo A, Jung M. Attenuated DNA damage repair by trichostatin a through BRCA1 suppression. Radiat Res. 2007;168:115–24.PubMedGoogle Scholar
  116. 116.
    Kim IA, Shin JH, Kim IH, et al. Histone deacetylase inhibitor-mediated radiosensitization of human cancer cells: class differences and the potential influence of p53. Clin Cancer Res. 2006;12:940–9.PubMedGoogle Scholar
  117. 117.
    Chinnaiyan P, Cerna D, Burgan WE, et al. Postradiation sensitization of the histone deacetylase inhibitor valproic acid. Clin Cancer Res. 2008;14:5410–5.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Entin-Meer M, Yang X, VandenBerg SR, et al. In vivo efficacy of a novel histone deacetylase inhibitor in combination with radiation for the treatment of gliomas. Neuro Oncol. 2007;9:82–8.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Kim JH, Shin JH, Kim IH. Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor. Int J Radiat Oncol Biol Phys. 2004;59:1174–80.PubMedGoogle Scholar
  120. 120.
    Lopez CA, Feng FY, Herman JM, Nyati MK, Lawrence TS, Ljungman M. Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation. Int J Radiat Oncol Biol Phys. 2007;69:214–20.PubMedGoogle Scholar
  121. 121.
    Siegel D, Hussein M, Belani C, et al. Vorinostat in solid and hematologic malignancies. J Hematol Oncol. 2009;2:31.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Kelly WK, Richon VM, O’Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res. 2003;9:3578–88.PubMedGoogle Scholar
  123. 123.
    O’Connor OA, Heaney ML, Schwartz L, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol. 2006;24:166–73.PubMedGoogle Scholar
  124. 124.
    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;111:1060–6.PubMedGoogle Scholar
  125. 125.
    Blumenschein GR Jr, 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;26:81–7.PubMedGoogle Scholar
  126. 126.
    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;19:964–9.PubMedGoogle Scholar
  127. 127.
    Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California cancer consortium study. Clin Cancer Res. 2008;14:7138–42.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Traynor AM, Dubey S, Eickhoff JC, et al. Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin oncology network phase II study. J Thorac Oncol. 2009;4:522–6.PubMedCentralPubMedGoogle Scholar
  129. 129.
    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;26:483–8.PubMedGoogle Scholar
  130. 130.
    Modesitt SC, Sill M, Hoffman JS, Bender DP, Gynecologic Oncology Group. A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study. Gynecol Oncol. 2008;109:182–6.PubMedGoogle Scholar
  131. 131.
    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;27:2052–8.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Wen PY, Puduvalli VK, Kuhn JG, et al. Phase I study of vorinostat in combination with temozolomide in patients with malignant gliomas. 2011; J Clin Oncol 29(suppl): abstr 2032.Google Scholar
  133. 133.
    Hummel TR, Wagner LM, Ahern CH, et al. A pediatric phase I trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a children’s oncology group phase I consortium study. 2011; J Clin Oncol 29(suppl): abstr 9579.Google Scholar
  134. 134.
    Chinnaiyan P, Chowdhary S, Potthast L, et al. Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma. Neuro Oncol. 2012;14:93–100.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Puduvalli VK, Penas-Prado M, Gilbert MR, et al. Phase I study of vorinostat combined with isotretinoin and carboplatin in adults with recurrent malignant gliomas. Neuro Oncol. 2010;12(suppl 4):iv69–78.Google Scholar
  136. 136.
    Friday BB, Anderson SK, Buckner J, et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro Oncol. 2012;14:215–21.PubMedCentralPubMedGoogle Scholar
  137. 137.
    Muscal JA, Thompson PA, Horton TM, et al. A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a children’s oncology group study. J Clin Oncol 29(suppl): abstr 9522, 2011.Google Scholar
  138. 138.
    Iwamoto FM, Lamborn KR, Kuhn JG, et al. A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American brain tumor consortium study 03–03. Neuro Oncol. 2011;13:509–16.PubMedCentralPubMedGoogle Scholar
  139. 139.
    Berg SL, Stone J, Xiao JJ, et al. Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother Pharmacol. 2004;54:85–8.PubMedGoogle Scholar
  140. 140.
    Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011;77:1156–64.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Bourg V, Lebrun C, Chichmanian RM, Thomas P, Frenay M. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann Oncol. 2001;12:217–9.PubMedGoogle Scholar
  142. 142.
    Oberndorfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol. 2005;72:255–60.PubMedGoogle Scholar
  143. 143.
    Su JM, Li X-N, Thompson P, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children’s oncology group report. Clin Cancer Res. 2011;17:589–97.PubMedCentralPubMedGoogle Scholar
  144. 144.
    Wolff JEA, Kramm C, Kortmann R-D, et al. Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma. J Neurooncol. 2008;90:309–14.PubMedGoogle Scholar
  145. 145.
    Masoudi A, Elopre M, Amini E, et al. Influence of valproic acid on outcome of high-grade gliomas in children. Anticancer Res. 2008;28:2437–42.PubMedGoogle Scholar
  146. 146.
    Verhaak RGW, Hoadley KA, Purdom E, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell. 2010;17:98–110.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.PubMedGoogle Scholar
  148. 148.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–9.PubMedGoogle Scholar
  149. 149.
    Reardon DA, Fink KL, Mikkelsen T, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008;26:5610–7.PubMedGoogle Scholar
  150. 150.
    Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol. 2009;27:3861–7.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28:1168–74.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010;28:4601–8.PubMedGoogle Scholar
  153. 153.
    Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.PubMedGoogle Scholar
  154. 154.
    Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13:916–26.PubMedGoogle Scholar
  155. 155.
    Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31:4085–91.PubMedGoogle Scholar
  156. 156.

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Rosemere Cancer CentreLancashire Teaching Hospitals NHS Foundation TrustPrestonUK

Personalised recommendations