A primer on the epigenetics of kidney fibrosis

Minerva Medica

Volumn 103, Issue 4, 2012, Pages 267-278

  Tampe, D ^a   Zeisberg, M ^a  

^a UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

Author keywords

Epigenesis, genetic; Fibrosis; Kidney

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; ABEXINOSTAT; ARYLBUTYRIC ACID DERIVATIVE; AZACITIDINE; BELINOSTAT; ENTINOSTAT; GIVINOSTAT; HYDRALAZINE; MOCETINOSTAT; PANOBINOSTAT; ROMIDEPSIN; TACEDINALINE; VALPROIC ACID; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; AMYOTROPHIC LATERAL SCLEROSIS; BLADDER CANCER; BRAIN ISCHEMIA; BRAIN TUMOR; BREAST CANCER; CARDIOVASCULAR DISEASE; CENTRAL NERVOUS SYSTEM TUMOR; CHRONIC KIDNEY DISEASE; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; COMORBIDITY; CROHN DISEASE; CUTANEOUS T CELL LYMPHOMA; CYSTIC FIBROSIS; DIABETES MELLITUS; DIAGNOSTIC PROCEDURE; DISEASE COURSE; DISEASE PREDISPOSITION; DNA METHYLATION; DNA MODIFICATION; EPIGENETICS; GENE TARGETING; GENETIC VARIABILITY; GLIOMA; HEAD AND NECK CANCER; HEPATIC ENCEPHALOPATHY; HISTONE MODIFICATION; HODGKIN DISEASE; HUMAN; HUNTINGTON CHOREA; HYPERTENSION; INSULIN RESISTANCE; JUVENILE RHEUMATOID ARTHRITIS; KIDNEY CARCINOMA; KIDNEY DISEASE; KIDNEY FIBROSIS; KIDNEY PELVIS CANCER; LEUKEMIA; LIVER CELL CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; LYMPHOMA; MELANOMA; MESOTHELIOMA; MULTIPLE MYELOMA; MYELODYSPLASTIC SYNDROME; MYELOPROLIFERATIVE DISORDER; NEUROBLASTOMA; NONHODGKIN LYMPHOMA; OVARY CANCER; PANCREAS CANCER; PLASMACYTOMA; PROSTATE CANCER; RECTUM CANCER; REVIEW; SMALL CELL CARCINOMA; SOLID TUMOR; SPINAL MUSCULAR ATROPHY; STOMACH CANCER; THALASSEMIA; TRANSCRIPTION INITIATION; TRANSITIONAL CELL CARCINOMA; TREATMENT PLANNING; URETER CANCER; URETHRA CANCER; UTERINE CERVIX CANCER;

ATROPHY; CHRONIC DISEASE; DISEASE PROGRESSION; DNA METHYLATION; EPIGENESIS, GENETIC; FIBROBLASTS; FIBROSIS; GENETIC MARKERS; HISTONES; HUMANS; KIDNEY; KIDNEY DISEASES; KIDNEY TUBULES; NEPHRITIS, INTERSTITIAL;

EID: 84867417768     PISSN: 00264806     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (123)

1. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis, J Am Soc Nephrol 2010;21:1819-34.
2. Wiig H, Tenstad O, Iversen PO, Kalluri R, Bjerkvig R. Interstitial fluid: the overlooked component of the tumor microenvironment? Fibrogenesis Tissue Repair 2010;3:12
3. Maeshima Y, Makino H. Angiogenesis and chronic kidney disease. Fibrogenesis Tissue Repair 2010;3:13.
4. van der Meer IM, Cravedi P, Remuzzi G. The role of renin angiotensin system inhibition in kidney repair. Fibrogenesis Tissue Repair 2010;3:7
5. Kanasaki M, Nagai T, Kitada M, Koya D, Kanasaki K: Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors. Fibrogenesis Tissue Repair 2011;4:25,
6. Zeisberg M. ANCA vasculitis meets epigenetics-closing in on the molecular roots of disease. Nephrol Dial Transplant 2011;26:1146-8.
7. Bird AP, Wolffe AP, Methylation-induced repression-belts, braces, and chromatin, Cell 1999;99:451-4. (Pubitemid 129746827)
8. Fujita N, Shimotake N, Ohki I, Chiba T, Saya H, Shirakawa M et al. Mechanism of transcriptional regulation by methyl-CpG binding protein MBD1. Mol Cell Biol 2000;20:5107-18 (Pubitemid 30431564)
9. Wade PA. Methyl CpG binding proteins: coupling chromatin architecture to gene regulation. Oncogene 2001;20:3166-73. (Pubitemid 32553572)
10. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349:2042-54. (Pubitemid 37448928)
11. Feinberg AP, Vogelstein B. Alterations in DNA methylation in human colon neoplasia, Semin Surg Oncol 1987;3:149-51. (Pubitemid 17112197)
12. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007;128:683-92. (Pubitemid 46273572)
13. Zhao L, Cui Q, Lu Z, Chen J. Aberrant methylation of RASSF2A in human pancreatic ductal adenocarcinoma and its relation to clinicopathologic features, Pancreas 2012;41:206-11.
14. Steinmann K, Richter AM, Dammann RH. Epigenetic silencing of erythropoietin in human cancers, Genes Cancer 2011;2:65-73.
15. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 1995;55:5195-9.
16. Vazquez I, Maicas M, Cervera J, Agirre X, Marin-Bejar O, Marcotegui N et al. Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia. Haematologica 2011;96:1448-56.
17. Humpherys D, Eggan K, Akutsu H, Hochedlinger K, Rideout WM, 3rd, Biniszkiewicz D et al. Epigenetic instability in ES cells and cloned mice. Science 2001;293:95-7. (Pubitemid 32625502)
18. Humpherys D, Eggan K, Akutsu H, Friedman A, Hochedlinger K, Yanagimachi R et al. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. Proc Natl Acad Sci U S A 2002;99:12889-94.
19. Jenuwein T, Allis CD: Translating the histone code. Science 2001;293:1074-80. (Pubitemid 32758077)
20. Dambacher S, Hahn M, Schotta G. Epigenetic regulation of development by histone lysine methylation. Heredity 2010;105:24-37.
21. Peterson CL, Laniel MA. Histones and histone modifications. Curr Biol 2004;14:R546-551.
22. Eddy AA. Molecular insights into renal interstitial fibrosis [editorial], J Am Soc Nephrol 1996;7:2495-508 (Pubitemid 27469555)
23. Zeisberg M, Strutz F, Muller GA. Role of fibroblast activation in inducing interstitial fibrosis. J Nephrol 2000(13 Suppl 3):S111-120.
24. Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kaibacher H, Salant DJ et al. Methylation determines fibroblast activation and fibrogenesis in the kidney, Nat Med 2010;16:544-50.
25. Rodemann HP, Muller GA. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis 1991;17:684-6.
26. Muller GA, Frank J, Rodemann HP, Engler-Blum G. Human renal fibroblast cell lines (tFKIF and tNKF) are new tools to investigate pathophysiologic mechanisms of renal interstitial fibrosis. Exp Nephrol 1995;3:127-33.
27. Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kaibacher H, Salant DJ et al. Methylation determines fibroblast activation and fibrogenesis in the kidney, Nat Med 2010;16:544-50
28. Kolfschoten IG, van Leeuwen B, Berns K, Mullenders J, Beijersbergen RL, Bernards R et al. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 2005;121:849-58 (Pubitemid 40806417)
29. Liu Q, Walker SA, Gao D, Taylor JA, Dai YF, Arkell RS et al. CAPRI and RASAL impose different modes of information processing on Ras due to contrasting temporal filtering of Ca2+. J Cell Biol 2005;170:183-90 (Pubitemid 41043801)
30. Tao H, Huang C, Yang JJ, Ma TT, Bian EB, Zhang L et al. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology 2011;290:327-33.
31. Smaldone S, Olivieri J, Gusella GL, Moroncini G, Gabrielu A, Ramirez F. Ha-Ras stabilization mediates pro-fibrotic signals in dermal fibroblasts. Fibrogenesis Tissue Repair 2011;4:8.
32. Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 2012;18:580-8
33. Galichon P, Hertig A. Epithelial to mesenchymal transition as a biomarker in renal fibrosis: are we ready for the bedside? Fibrogenesis Tissue Repair 2011;4:11.
34. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429-37.
35. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 2010;16:535-43, 531.
36. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E: Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/NCoR, Mol Cell 2002;9:45-57. (Pubitemid 34127770)
37. Osada H, Tatematsu Y, Saito H, Yatabe Y, Mitsudomi T, Takahashi T. Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients, Int J Cancer 2004;112:26-32. (Pubitemid 39249488)
38. Hagelkruys A, Sawicka A, Rennmayr M, Seiser C. The biology of HDAC in cancer: the nuclear and epigenetic components. Handb Exp Pharmacol 2011;13-37.
39. Pang M, Kothapally J, Mao H, Tolbert E, Ponnusamy M, Chin YE et al. Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy, Am J Physiol Renal Physiol 2009;297:F996-F1005.
40. Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta 1-induced renal injury, Am J Physiol Renal Physiol 2009;297:F729-739
41. Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia, Lancet 2003;361:1693-9. (Pubitemid 36577442)
42. Nanayakkara PW, Kiefte-de Jong JC, Stehouwer CD, van Ittersum FJ, Olthof MR, Kok RM et al. Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2-4 chronic kidney disease. Nephrol Dial Transplant 2008;23:2586-92.
43. Stenvinkel P, Karimi M, Johansson S, Axelsson J, Suliman M, Lindholm B et al. Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease? J Intern Med 2007;261:488-99. (Pubitemid 46587721)
44. Sapienza C, Lee J, Powell J, Erinle O, Yafai F, Reichert J et al. DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy. Epigenetics 2011;6:20-8.
45. Daujat S, Zeissler U, Waldmann T, Happel N, Schneider R. HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding, J Biol Chem 2005;280:38090-5. (Pubitemid 41642423)
46. Clarke AS, Lowell JE, Jacobson SJ, Pillus L. Esa1p is an essential histone acetyltransferase required for cell cycle progression. Mol Cell Biol 1999;19:2515-26. (Pubitemid 29144495)
47. Kimura A, Horikoshi M. Tip60 acetylates six lysines of a specific class in core histones in vitro, Genes Cells 1998;3:789-800. (Pubitemid 29098935)
48. Schiltz RL, Mizzen CA, Vassilev A, Cook RG, Allis CD, Nakatani Y. Overlapping but distinct patterns of histone acetylation by the human coactivators p300 and PCAF within nucleosomal substrates, J Biol Chem 1999;274:1189-92.
49. Suka N, Suka Y, Carmen AA, Wu J, Grunstein M. Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin. Mol Cell 2001;8:473-9. (Pubitemid 32831564)
50. Maile T, Kwoczynski S, Katzenberger RJ, Wassarman DA, Sauer F. TAF1 activates transcription by phosphorylation of serine 33 in histone H2B. Science 2004;304:1010-4. (Pubitemid 38638099)
51. Robzyk K, Recht J, Osley MA. Rad6-dependent ubiquitination of histone H2B in yeast. Science 2000;287:501-4.
52. Grant PA, Eberharter A, John S, Cook RG, Turner BM, Workman JL et al. Expanded lysine acetylation specificity of Gcn5 in native complexes, J Biol Chem 1999;274:5895-900. (Pubitemid 29109247)
53. Xu F, Zhang K, Grunstein M. Acetylation in histone H3 globular domain regulates gene expression in yeast. Cell 2005;121:375-85. (Pubitemid 40692298)
54. Wang H, Cao R, Xia L, Erdjument-Bromage H, Borchers C, Tempst P et al. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol Cell 2001;8:1207-17. (Pubitemid 34084993)
55. Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V et al. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II, Mol Cell Biol 2003;23:4207-18. (Pubitemid 36666424)
56. Krogan NJ, Dover J, Wood A, Schneider J, Heidt J, Boateng MA et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elo57. Daujat S, Bauer UM, Shah V, Turner B, Berger S, Kouzarides T. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr Biol 2002;12:2090-7.
57. Strahl BD, Briggs SD, Brame CJ, Caldwell JA, Koh SS, Ma H et al. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1, Curr Biol 2001;11:996-1000.
58. Nathan D, Ingvarsdottir K, Sterner DE, Bylebyl GR, Dokmanovic M, Dorsey JA et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications, Genes Dev 2006;20:966-76.
59. Tachibana M, Sugimoto K, Fukushima T, Shinkai Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem 2001;276:25309-17.
60. Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S. Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes, Mol Cell Biol 2004;24:9630-45. (Pubitemid 39391698)
61. Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y et al. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin, Mol Cell 2002;9:1201-13.
62. Zhang L, Eugeni EE, Parthun MR, Freitas MA Identification of novel histone post-translational modifications by peptide mass fingerprinting. Chromosoma 2003;112:77-86. (Pubitemid 37150565)
63. Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression, Proc Natl Acad Sci U S A 2003;100:13225-30. (Pubitemid 37444723)
64. Bolden JE, Peart MJ, Johnstone RW Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006;5:769-84. (Pubitemid 44348499)
65. Radford J, Davies A, Dyer M, Sureda A, Engert A, Shen A et al. Efficacy of panobinostat in phase II study in patients with relapsed/refractory Hodgkin lymphoma (HL) after high-dose chemotherapy with autologous stem cell transplant. Brit J Haematol 2010;149:2-3.
66. Duvic M, Becker JC, Dalle S, Vanaclocha F, Bernengo MG, Lebbe C et al. Phase II trial of oral Panobinostat (LBH589) in patients with refractory cutaneous t-cell lymphoma (CTCL). Blood 2008;112:370.
67. Budman DR, Tai JL, Calabro A, John V. The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. Invest New Drug 2011;29:1224-9.
68. Pettazzoni P, Pizzimenti S, Toaldo C, Sotomayor P, Tagliavacca L, Liu S et al. Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells. Free Radical Bio Med 2011;50:313-22.
69. Conte P, Campone M, Pronzato P, Amadori D, Frank R, Schuetz F et al. Phase I trial of panobinostat (LBH589) in combination with trastuzumab in pretreated HER2-positive metastatic breast cancer (mBC): Preliminary safety and tolerability results, Journal of Clinical Oncology 2009;27.
70. De Marinis F, Atmaca A, Al-Batran S, Tiseo M, Ciuffreda L, Gridelli C et al. Results of a multicenter phase II Trial with the deacetylase inhibitor (Daci) panobinostat in relapsed small cell lung cancer (Sclc) patients. Ann Oncol 2010;21:148-9.
71. Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM et al. A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemoth Pharm 2010;66:181-9.
72. Cashen A, Juckett M, Jumonville A, Litzow M, Flynn PJ, Eckardt J et al. Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS). Ann Hematol 2012;91:33-8.
73. Lassen U, Molife LR, Sorensen M, Engelholm SA, Vidal L, Sinha R et al. 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. Br J Cancer 2010;103:12-7.
74. Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P et al. Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Cancer 2010;46:1573-9.
75. Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 2008;81:170-6.
76. Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C, Pescosta N et al. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann Hematol 2010;89:185-90.
77. Furlan A, Monzani V, Reznikov LL, Leoni F, Fossati G, Modena D et al. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol Med 2011;17:353-62.
78. Evens AM, Ai WY, Balasubramanian S, Sirisawad M, Mani C, Guerra M et al. Phase I analysis of the safety and pharmacodynamics of the novel broad spectrum historic deacetylase inhibitor (HDACi) PCI-24781 in relapsed and refractory lymphoma. Blood 2009;114:1067.
79. Gilbert J, Baker SD, Bowling MK, Grochow L, Figg WD, Zabelina Y et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 2001;7:2292-300. (Pubitemid 32751627)
80. Lin J, Gilbert J, Rudek MA, Zwiebel JA, Gore S, Jiemjit A et al. A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors, Clin Cancer Res 2009;15:6241-9.
81. Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99-106.
82. Camacho LH, Olson J, Tong WP, Young CW, Spriggs DR, Malkin MG. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors, Invest New Drugs 2007;25:131-8. (Pubitemid 46020871)
83. Clarke KO, Ludeman SM, Springer JB, Colvin OM, Lea MA, Harrison LE. Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells. J Pharm Sci 2002;91:1054-64. (Pubitemid 34640930)
84. Ebbel EN, Leymarie N, Schiavo S, Sharma S, Gevorkian S, Hersch S et al. Identification of phenylbutyrate-generated metabolites in Huntington disease patients using parallel liquid chromatography/electrochemical array/mass spectrometry and off-line tandem mass spectrometry. Anal Biochem 2010;399:152-61.
85. Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 2006;20:212-7. (Pubitemid 43148657)
86. Arakawa Y, Saito S, Yamada H, Aiba K. Simultaneous treatment with camptothecin and valproic acid suppresses induction of Bcl-X(L) and promotes apoptosis of MCF-7 breast cancer cells. Apoptosis 2009;14:1076-85.
87. Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia, Ann Hematol 2005;84(Suppl 1):61-6.
88. Raffoux E, Cras A, Recher C, Boelle PY, de Labarthe A, Turlure P et al. Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget 2010;1:34-42.
89. Rocca A, Minucci S, Tosti G, Croci D, Contegno F, Ballarini M et al. A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma. Br J Cancer 2009;100:28-36.
90. Gibbons HM, Smith AM, Teoh HH, Bergin PM, Mee EW, Faull RL et al. Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures. Neurobiol Dis 2011;41:96-103.
91. Swoboda KJ, Scott CB, Reyna SP, Prior TW, LaSalle B, Sorenson SL et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009;4.
92. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH 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.
93. Whitehead RP, Rankin C, Hoff PM, Gold PJ, Billingsley KG, Chapman RA et al. Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336). Invest New Drugs 2009;27:469-75
94. Otterson GA, Hodgson L, Pang H, Vokes EE. Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304), J Thorac Oncol 2010;5:1644-8.
95. Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S, Riggs CE et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC), Ann Oncol 2010;21:109-13.
96. Iwamoto FM, Lamborn KR, Kuhn JG, Wen PY, Yung WK, Gilbert MR 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.
97. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011;117:5827-34.
98. Niesvizky R, Ely S, Mark T, Aggarwal S, Gabrilove JL, Wright JJ et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma, Cancer 2011;117:336-42.
99. Wardley AM, McCaffrey J, Crown J, Stein R, Malik Z, Rea D et al. Preliminary Phase II Data Suggest That Entinostat (SNDX275), a Class I Selective Histone Deacetylase Inhibitor (HDACi), May Resensitize Breast Cancer Patients Progressing on Aromataste Inhibitor (AI) Therapy to Their AI Therapy. Cancer Res 2009;69:860s.
100. Juergens R, Vendetti F, Coleman B, Sebree R, Belinsky S, Rudek M et al. A phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC): an interim analysis, J Thorac Oncol 2009;4:S306-S307.
101. Younes A, Hernandez F, Bociek RG, Kasamon YL, Lee P, Gore L et al. ENGAGE-501: phase 2 Study investigating the role of epigenetic therapy with entinostat (SNDX-275) in relapsed and refractory Hodgkin's lymphoma (HL), interim results. Blood 2010;116:1614-5.
102. Witta S, Jotte R, Neubauer M, Spire A, Ruxer R, Konduri K et al. Analysis of cross-over portion of Encore-401, a randomized, double-blind, placebo-controlled phase 2 study of erlotinib with and without entinostat, a class 1 isoform selective Histone Deacetylase Inhibitor (Hdac) in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011;6:S1314-S1314.
103. Prakash S, Foster BJ, Meyer M, Wozniak A, Heilbrun LK, Flaherty L et al. Chronic oral administration of CI-994: A phase 1 study. Invest New Drug 2001;19:1-11. (Pubitemid 32209780)
104. Richards DA, Boehm KA, Waterhouse DM, Wagener DJ, Krishnamurthi SS, Rosemurgy A 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;17:1096-102. (Pubitemid 43985245)
105. Pauer LR, Olivares J, Cunningham C, Williams A, Grove W, Kraker G 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. (Pubitemid 39665354)
106. Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008;112:981-9.
107. Siu LL, Pili R, Duran I, Messersmith WA, Chen EX, Sullivan R et al. Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors, J Clin Oncol 2008;26:1940-7.
108. Blum KA, Advani A, Fernandez L, Van Der Jagt R, Brandwein J, Kambhampati S et al. Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia. Br J Haematol 2009;147:507-14.
109. Winton EF, Hearn EB, Martelo O, Presant CA, Adler S, Vogler WR et al. Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: a phase I-II trial of the Southeastern Cancer Study Group. Cancer Treat Rep 1985;69:807-11. (Pubitemid 15229419)
110. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 2005;10:176-82. (Pubitemid 40463154)
111. Zhang B, Huang T, Liu K, Chen J, Wang G. Effects of 5-Aza-CdR on cell proliferation of breast cancer cell line MDA-MB-435S and expression of maspin gene. J Huazhong Univ Sci Technolog Med Sci 2007;27:543-6.
112. Sonpavde G, Aparicio A, Guttierez I, Boehm KA, Hutson TE, Berry WR et al. Phase II study of azacitidine to restore responsiveness of prostate cancer to hormonal therapy. Clin Genitourin Cancer 2007;5:457-9. (Pubitemid 351219701)
113. Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF et al. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer 2011;117:1661-9.
114. Momparler RL, Bouffard DY, Momparler LF, Dionne J, Belanger K, Ayoub J. Pilot phase I-II study on 5-aza-2′-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anticancer Drugs 1997;8:358-68. (Pubitemid 27204954)
115. Schwartsmann G, Schunemann H, Gorini CN, Filho AF, Garbino C, Sabini G et al. A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer. Invest New Drugs 2000;18:83-91. (Pubitemid 30175899)
116. Pohlmann P, DiLeone LP, Cancella AI, Caldas AP, Dal Lago L, Campos O, Jr. et al. Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix, Am J Clin Oncol 2002;25:496-501. (Pubitemid 35154957)
117. Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate, J Clin Oncol 2005;23:3948-56. (Pubitemid 46218698)
118. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006;106:1794-803.
119. George RE, Lahti JM, Adamson PC, Zhu K, Finkelstein D, Ingle AM et al. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer 2010;55:629-38.
120. Etteldorf JN, Smith JD, Johnson C. The effect of reserpine and its combination with hydralazine on blood pressure and renal hemodynamics during the hypertensive phase of acute nephritis in children. J Pediatr 1956;48:129-39.
121. Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 2007;18:1529-38.
122. Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, Gonzalez-Fierro A, de la Cruz-Hernandez E et al. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results. Med Oncol 2011;28(Suppl 1):S540-6.
123. Candelaria M, Herrera A, Labardini J, Gonzalez-Fierro A, Trejo-Becerril C, Taja-Chayeb L et al. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 2011;90:379-87.