Histone deacetylase inhibitors in hematological malignancies and solid tumors

다국어 초록 (Multilingual Abstract)

Histone deacetylase (HDAC) inhibitors areemerging as promising anticancer drugs. Because aberrantactivity and expression of HDACs have been implicated invarious cancer types, a wide range of HDAC inhibitors arebeing investigated as anticancer agents. Furthermore, dueto the demonstrable anticancer activity in both in vitro andin vivo studies, numerous HDAC inhibitors have undergonea rapid phase of clinical development in variouscancer types, either as a monotherapy or in combinationwith other anticancer agents. Although preclinical trialsshow that HDAC inhibitors have a variety of biologicaleffects across multiple pathways, including regulation ofgene expression, inducing apoptosis and cell cycle arrest,inhibiting angiogenesis, and regulation of DNA damageand repair, the mechanism by which the clinical activity ismediated remains unclear. Understanding the mechanismsof anticancer activity of HDAC inhibitors is essential notonly for rational drug design for targeted therapies, but forthe design of optimized clinical protocols. This paperdescribes the links between HDACs and cancer, and theunderlying mechanisms of action of HDAC inhibitorsagainst hematological malignancies and solid tumors.
Further, this review presents the clinical outcomes ofvorinostat, romidepsin, and belinostat, which are approvedby the United States Food and Drug Administration for thetreatment of lymphomas.

참고문헌 (Reference)

• 1 Hitomi, T., "p15(INK4b)in HDAC inhibitor-induced growth arrest" 554 : 347-350, 2003
• 2 Traynor, A.M., "Vorinostat(NSC# 701852)in patients with relapsed nonsmall cell lung cancer : A Wisconsin Oncology Network phase II study" 4 : 522-526, 2009
• 3 Bradley, D., "Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy(National Cancer Institute Trial 6862) : Trial results and interleukin-6 analysis : A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium" 115 : 5541-5549, 2009
• 4 Halkidou, K., "Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer" 59 : 177-189, 2004
• 5 Hayashi, A, "Type-specific roles of histone deacetylase(HDAC)overexpression in ovarian carcinoma : HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin" 127 : 1332-1346, 2010
• 6 Jin, Y.H., "Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation" 279 : 29409-29417, 2004
• 7 Gaughan, L., "Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor" 277 : 25904-25913, 2002
• 8 Ropero, S., "The role of histone deacetylases(HDACs)in human cancer" 1 : 19-25, 2007
• 9 Hutt, D.M., "The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition" 9 : e106224-, 2014
• 10 Zhang, X.D, "The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells" 3 : 425-435, 2004
• 11 Ruefli, A.A., "The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species" 98 : 10833-10838, 2001
• 12 Fischle, W, "The emerging role of class II histone deacetylases" 79 : 337-348, 2001
• 13 Firestein, R., "The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth" 3 : e2020-, 2008
• 14 Ashkenazi, A., "Targeting death and decoy receptors of the tumour-necrosis factor superfamily" 2 : 420-430, 2002
• 15 Zheng, G, "Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2" 280 : 40773-40781, 2005
• 16 Konstantinopoulos, P.A, "Suberoylanilide hydroxamic acid(SAHA)enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer" 133 : 599-606, 2014
• 17 Younes, A., "Suberoylanilide hydroxamic acid suppresses inflammationinduced neovascularization" 92 : 879-885, 2014
• 18 Zhou, H, "Suberoylanilide hydroxamic acid suppresses inflammation-induced neovascularization" 92 : 879-885, 2014
• 19 Richon, V.M., "Second generation hybrid polar compounds are potent inducers of transformed cell differentiation" 93 : 5705-5708, 1996
• 20 Yuan, Z.L, "STAT3 dimerization regulated by reversible acetylation of a single lysine residue" 307 : 269-273, 2005
• 21 Gobinet, J., "SHP represses transcriptional activity via recruitment of histone deacetylases" 44 : 6312-6320, 2005
• 22 Ungerstedt, J.S., "Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors" 102 : 673-678, 2005
• 23 Lin, R.J., "Role of the histone deacetylase complex in acute promyelocytic leukaemia" 391 : 811-814, 1998
• 24 Coiffier, B., "Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy" 30 : 631-636, 2012
• 25 Kim, S.H., "Regulation of the HIF-1alpha stability by histone deacetylases" 17 : 647-651, 2007
• 26 Martı ´nez-Balba ´s, M.A., "Regulation of E2F1 activity by acetylation" 19 : 662-671, 2000
• 27 Osada, H, "Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients" 112 : 26-32, 2004
• 28 Lynch Jr., D.R., "QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat : A case report and review of the literature" 19 : 434-438, 2012
• 29 Straus, S.M, "Prolonged QTc interval and risk of sudden cardiac death in a population of older adults" 47 : 362-367, 2006
• 30 Marquard, L., "Prognostic significance of the therapeutic targets histone deacetylase 1, 2, 6 and acetylated histone H4 in cutaneous T-cell lymphoma" 53 : 267-277, 2008
• 31 Olsen, E.A., "Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma" 25 : 3109-3115, 2007
• 32 Molife, L.R., "Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor(HDACi)romidepsin in metastatic castration-resistant prostate cancer(CRPC)" 21 : 109-113, 2010
• 33 Blumenschein Jr., G.R, "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" 26 : 81-87, 2008
• 34 Haigentz Jr., M., "Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer" 48 : 1281-1288, 2012
• 35 Mackay, H.J., "Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary(LMP)ovarian tumours" 46 : 1573-1579, 2010
• 36 Whitehead, R.P., "Phase II trial of romidepsin(NSC-630176)in previously treated colorectal cancer patients with advanced disease : A Southwest Oncology Group study(S0336)" 27 : 469-475, 2009
• 37 Kirschbaum, M., "Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma" 29 : 1198-1203, 2011
• 38 Cashen, A, "Phase II study of the histone deacetylase inhibitor belinostat(PXD101)for the treatment of myelodysplastic syndrome(MDS)" 91 : 33-38, 2012
• 39 Otterson, G.A, "Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer(Cancer and Leukemia Group B 30304)" 5 : 1644-1648, 2010
• 40 Ramalingam, S.S., "Phase II study of belinostat(PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma" 4 : 97-101, 2009
• 41 Giaccone, G., "Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors" 29 : 2052-2059, 2011
• 42 Piekarz, R.L., "Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma" 27 : 5410-5417, 2009
• 43 Kelly, W.K., "Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer" 23 : 3923-3931, 2005
• 44 Duvic, M., "Phase 2 trial of oral vorinostat(suberoylanilide hydroxamic acid, SAHA)for refractory cutaneous T-cell lymphoma(CTCL)" 109 : 31-39, 2006
• 45 Garcia-Manero, G., "Phase 1 study of the histone deacetylase inhibitor vorinostat(suberoylanilide hydroxamic acid [SAHA])in patients with advanced leukemias and myelodysplastic syndromes" 111 : 1060-1066, 2008
• 46 Sandor, V, "P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228" 83 : 817-825, 2000
• 47 Kawai, H., "Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor alpha" 107 : 353-358, 2003
• 48 Mal, A., "MyoD is functionally linked to the silencing of a muscle-specific regulatory gene prior to skeletal myogenesis" 100 : 1735-1739, 2003
• 49 Seo, S.Y., "Multi-targeted hybrids based on HDAC inhibitors for anti-cancer drug discovery" 35 : 197-200, 2012
• 50 Strevel, E.L., "Molecularly targeted oncology therapeutics and prolongation of the QT interval" 25 : 3362-3371, 2007
• 51 Gregoretti, I.V., "Molecular evolution of the histone deacetylase family : Functional implications of phylogenetic analysis" 338 : 17-31, 2004
• 52 Mwakwari, S.C., "Macrocyclic histone deacetylase inhibitors" 10 : 1423-1440, 2010
• 53 Fournel, M, "MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo" 7 : 759-768, 2008
• 54 Fraga, M.F, "Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer" 37 : 391-400, 2005
• 55 Ho ¨rlein, A.J., "Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor" 377 : 397-404, 1995
• 56 Yang, W.M., "Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family" 272 : 28001-28007, 1997
• 57 Sutheesophon, K., "Involvement of the tumor necrosis factor(TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide(FK228)" 203 : 387-397, 2005
• 58 Bertrand, P., "Inside HDAC with HDAC inhibitors" 45 : 2095-2116, 2010
• 59 Zhao, Y., "Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim" 102 : 16090-16095, 2005
• 60 Insinga, A., "Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway" 11 : 71-76, 2005
• 61 Lee, Y.M., "Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity" 300 : 241-246, 2003
• 62 Bali, P., "Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 : A novel basis for antileukemia activity of histone deacetylase inhibitors" 280 : 26729-26734, 2005
• 63 Song, J., "Increased expression of histone deacetylase 2 is found in human gastric cancer" 113 : 264-268, 2005
• 64 Hu, E., "Identification of novel isoform-selective inhibitors within class I histone deacetylases" 307 : 720-728, 2003
• 65 Peart, M.J., "Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors" 102 : 3697-3702, 2005
• 66 Johnstone, R.W, "Histone-deacetylase inhibitors : Novel drugs for the treatment of cancer" 1 : 287-299, 2002
• 67 de Ruijter, A.J., "Histone deacetylases(HDACs) : Characterization of the classical HDAC family" 370 : 737-749, 2003
• 68 Kim, M.S, "Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes" 7 : 437-443, 2001
• 69 Marks, P., "Histone deacetylases and cancer : Causes and therapies" 1 : 194-202, 2001
• 70 Park,S.Y, "Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer" 25 : 1677-1681, 2011
• 71 Weichert, W., "Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy" 98 : 604-610, 2008
• 72 Montgomery, R.L., "Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility" 21 : 1790-1802, 2007
• 73 Geng, L., "Histone deacetylase(HDAC)inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer" 66 : 11298-11304, 2006
• 74 Qiu, L., "Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells" 11 : 2069-2083, 2000
• 75 Sawa, H., "Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the Bcl-2-related protein Bad" 18 : 109-114, 2001
• 76 Burgess, A., "Histone deacetylase inhibitors specifically kill nonproliferating tumour cells" 23 : 6693-6701, 2004
• 77 Chen, C.S., "Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation" 67 : 5318-5327, 2007
• 78 Fath, D.M., "Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha" 281 : 13612-13619, 2006
• 79 Munshi, A., "Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity" 11 : 4912-4922, 2005
• 80 Kong, X., "Histone deacetylase inhibitors induce VHL and ubiquitinindependent proteasomal degradation of hypoxia-inducible factor 1alpha" 26 : 2019-2028, 2006
• 81 Rosato, R.R., "Histone deacetylase inhibitors : Insights into mechanisms of lethality" 9 : 809-924, 2005
• 82 Yamashita, Y, "Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells" 103 : 572-576, 2003
• 83 Koprinarova, M., "Histone deacetylase inhibitor sodium butyrate enhances cellular radiosensitivity by inhibiting both DNA nonhomologous end joining and homologous recombination" 10 : 970-977, 2011
• 84 Richon, V.M, "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation" 97 : 10014-10019, 2000
• 85 Wang, J.C., "Histone deacetylase in chronic lymphocytic leukemia" 81 : 325-329, 2011
• 86 Oehme, I., "Histone deacetylase 8 in neuroblastoma tumorigenesis" 15 : 91-99, 2009
• 87 Kato, H., "Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity" 279 : 41966-41974, 2004
• 88 Li, D., "Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells" 5 : 214-223, 2014
• 89 Atsumi, A., "Histone deacetylase 3(HDAC3)is recruited to target promoters by PML–RARalpha as a component of the N-CoR co-repressor complex to repress transcription in vivo" 345 : 1471-1480, 2006
• 90 Ozawa, Y., "Histone deacetylase 3 associates with and represses the transcription factor GATA-2" 98 : 2116-2123, 2001
• 91 Gui, C.Y, "Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1" 101 : 1241-1246, 2004
• 92 Norton, V.G., "Histone acetylation reduces nucleosome core particle linking number change" 57 : 449-457, 1989
• 93 Grunstein, M., "Histone acetylation in chromatin structure and transcription" 389 : 349-352, 1997
• 94 Kouzarides, T., "Histone acetylases and deacetylases in cell proliferation" 9 : 40-48, 1999
• 95 Ouaı ¨ssi, M., "High histone deacetylase 7(HDAC7)expression is significantly associated with adenocarcinomas of the pancreas" 15 : 2318-2328, 2008
• 96 Kovacs, J.J., "HDAC6 regulates Hsp90 acetylation and chaperonedependent activation of glucocorticoid receptor" 18 : 601-607, 2005
• 97 Serrador, J.M., "HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization" 20 : 417-428, 2004
• 98 Feng, G.W., "HDAC5 promotes cell proliferation in human hepatocellular carcinoma by up-regulating Six1 expression" 18 : 811-816, 2014
• 99 Milde, T., "HDAC5 and HDAC9 in medulloblastoma : Novel markers for risk stratification and role in tumor cell growth" 16 : 3240-3252, 2010
• 100 Jung, K.H., "HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins" 113 : 2167-2177, 2012
• 101 Deubzer, H.E., "HDAC11 is a novel drug target in carcinomas" 132 : 2200-2208, 2013
• 102 Xie, H.J., "HDAC1 inactivation induces mitotic defect and caspase independent autophagic cell death in liver cancer" 7 : e34265-, 2012
• 103 Stypula-Cyrus, Y., "HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure" 8 : e64600-, 2013
• 104 Whittaker, S.J., "Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma" 28 : 4485-4491, 2010
• 105 Furumai, R., "FK228(depsipeptide)as a natural prodrug that inhibits class I histone deacetylases" 62 : 4916-4921, 2002
• 106 Mann, B.S, "FDA approval summary : Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma" 12 : 1247-1252, 2007
• 107 Minamiya, Y., "Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung" 74 : 300-304, 2011
• 108 Vansteenkiste, J., "Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or nonsmall cell lung cancer" 26 : 483-488, 2008
• 109 Amann, J.M., "ETO, a target of t(8;21)in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain" 21 : 6470-6483, 2001
• 110 Chen, L.f., "Duration of nuclear NF-kappaB action regulated by reversible acetylation" 293 : 1653-1657, 2001
• 111 Cha, T.L., "Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2–M arrest and apoptosis of renal cancer cells" 15 : 840-850, 2009
• 112 "Drugs@FDA"
• 113 "Drugs. Romidepsin"
• 114 "Drugs. Belinostat"
• 115 Wolbrette, D., "Drugs that cause torsades de pointes and increase the risk of sudden cardiac death" 6 : 379-384, 2004
• 116 El-Khoury, V, "Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia" 28 : 1636-1646, 2014
• 117 Mu ¨ller, B.M., "Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer—Overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression" 13 : 215-, 2013
• 118 Moreno, D.A., "Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia" 150 : 665-673, 2010
• 119 Khan, N., "Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors" 409 : 581-589, 2008
• 120 Luo, J, "Deacetylation of p53 modulates its effect on cell growth and apoptosis" 408 : 377-381, 2000
• 121 Bakkenist, C.J., "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation" 421 : 499-506, 2003
• 122 Decroos, C, "Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders" 9 : 2157-2164, 2014
• 123 Gao, L., "Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family" 277 : 25748-25755, 2002
• 124 Quint, K, "Clinical significance of histone deacetylases 1, 2, 3, and 7 : HDAC2 is an independent predictor of survival in HCC" 459 : 129-139, 2011
• 125 Qian, D.Z, "Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha" 66 : 8814-8821, 2006
• 126 Verdin, E., "Class II histone deacetylases : Versatile regulators" 19 : 286-293, 2003
• 127 Bertos, N.R., "Class II histone deacetylases : Structure, function, and regulation" 79 : 243-252, 2001
• 128 Fritzsche, F.R., "Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer" 8 : 381-, 2008
• 129 Adams, H., "Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin’s lymphoma" 14 : 577-584, 2010
• 130 Weichert, W., "Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer : Specific role of class I histone deacetylases in vitro and in vivo" 14 : 1669-1677, 2008
• 131 Bantscheff, M., "Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes" 29 : 255-265, 2011
• 132 Bradner, J.E., "Chemical phylogenetics of histone deacetylases" 6 : 238-243, 2010
• 133 Bates, S.E, "Challenges of evaluating the cardiac effects of anticancer agents" 12 : 3871-3874, 2006
• 134 Shah, M.H., "Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors" 12 : 3997-4003, 2006
• 135 Piekarz,R.L., "Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma" 12 : 3762-3773, 2006
• 136 Zgouras, D., "Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1alpha nuclear translocation" 300 (300): 832-838, 2003
• 137 Zhang, Y., "Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis" 13 : 129-140, 2006
• 138 "BELIEF study"
• 139 Weichert, W., "Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer : A retrospective analysis" 9 : 139-148, 2008
• 140 Burz, C., "Apoptosis in cancer : Key molecular signaling pathways and therapy targets" 48 : 811-821, 2009
• 141 Heltweg, B., "Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes" 66 : 4368-4377, 2006
• 142 Bagnes, C., "Antineoplastic chemotherapy induced QTc prolongation" 5 : 93-96, 2010
• 143 Bolden, J.E., "Anticancer activities of histone deacetylase inhibitors" 5 : 769-784, 2006
• 144 Pe ´rez-Perarnau, A., "Analysis of apoptosis regulatory genes altered by histone deacetylase inhibitors in chronic lymphocytic leukemia cells" 6 : 1228-1235, 2011
• 145 Noh, E.J., "An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcriptiondependent manner" 378 : 326-331, 2009
• 146 Watamoto, K, "Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation" 22 : 9176-9184, 2003
• 147 Gelmetti, V., "Aberrant recruitment of the nuclear receptor corepressor–histone deacetylase complex by the acute myeloid leukemia fusion partner ETO" 18 : 7185-7191, 1998
• 148 Ropero, S, "A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition" 38 : 566-569, 2006
• 149 Mal, A., "A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD : Inhibition of the myogenic program" 20 : 1735-1739, 2001
• 150 Luu, T.H., "A phase II trial of vorinostat(suberoylanilide hydroxamic acid)in metastatic breast cancer : A California Cancer Consortium study" 14 : 7138-7142, 2008
• 151 Modesitt, S.C., "A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma : A Gynecologic Oncology Group study" 109 : 182-186, 2008
• 152 Stadler, W.M, "A phase II study of depsipeptide in refractory metastatic renal cell cancer" 5 : 57-60, 2006
• 153 Iwamoto, F.M., "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" 13 : 509-516, 2011
• 154 Lassen, U., "A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours" 103 : 12-17, 2010
• 155 Steele, N.L., "A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors" 14 : 804-810, 2008
• 156 Kim, M.K., "A novel hydroxamic acid derivative, MHY218, induces apoptosis and cell cycle arrest through downregulation of NF-jB in HCT116 human colon cancer cells" 44 : 256-264, 2014
• 157 Ogura, M., "A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma" 165 : 768-776, 2014
• 158 Curran,M.E., "A molecular basis for cardiac arrhythmia : HERG mutations cause long QT syndrome" 80 : 795-803, 1995
• 159 Foss, F., "A Phase II trial of Belinostat(PXD101)in patientswith relapsed or refractory peripheral or cutaneous T-cell lymphoma(Abstract)" 2014