Archives of Toxicology

, Volume 88, Issue 9, pp 1651–1668 | Cite as

Epigenetic drugs against cancer: an evolving landscape

  • Antonella Di Costanzo
  • Nunzio Del Gaudio
  • Antimo Migliaccio
  • Lucia Altucci
Review Article

Abstract

Alteration of the chromatin orchestra seems to play a critical role in cancer. In recent years, in-depth studies of epigenetic machinery and its deregulation have led to the development and use of a wide range of modulatory molecules directed not only at chromatin enzymes (histone acetyltransferases, histone deacetylases, histone methyltransferases, histone demethylases and DNA methyltransferases) but also toward the emerging class of chromatin-associated proteins, so-called “histone readers.” Chromatin modifiers are attractive therapeutic targets for the development of new cancer therapies. Many are currently approved by the US Food and Drug Administration and used to treat different malignancies. Specifically, inhibitors of DNA methyltransferases, such as azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome, while inhibitors of histone deacetylases, including vorinostat and romidepsin, have been approved for cutaneous T-cell lymphoma. The bromodomain and extra-terminal inhibitors JQ1, IBET762 and IBET151 have performed extremely well in preclinical settings, suggesting that they may be promising molecules for the treatment of some type of tumors. This review focuses on epidrugs and their possible application, with particular emphasis on their mechanism of action as well as their present status in clinical and preclinical trials.

Keywords

Epigenetics Chromatin modulation Cancer Drug discovery 

Notes

Acknowledgments

This work was supported by: EU, Blueprint project no. 282510; the Italian Flag Project: EPIGEN; AIRC No. 11812; PRIN-2012. We apologize to the authors whose work we could not cite due to reference restrictions. We wish to thank C. Fisher for linguistic editing of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Allis CD, Berger SL, Cote J et al (2007) New nomenclature for chromatin-modifying enzymes. Cell 131(4):633–636. doi: 10.1016/j.cell.2007.10.039 PubMedGoogle Scholar
  2. Amato RJ, Stephenson J, Hotte S et al (2012) MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma. Cancer Invest 30(5):415–421. doi: 10.3109/07357907.2012.675381 PubMedGoogle Scholar
  3. Amiri-Kordestani L, Luchenko V, Peer CJ et al (2013) Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res 19(16):4499–4507. doi: 10.1158/1078-0432.CCR-13-0095 PubMedGoogle Scholar
  4. Andreadi C, Britton RG, Patel KR, Brown K (2014) Resveratrol-sulfates provide an intracellular reservoir for generation of parent resveratrol, which induces autophagy in cancer cells. Autophagy 10(3):524–525. doi: 10.4161/auto.27593 PubMedGoogle Scholar
  5. Armas-Pineda C, Arenas-Huertero F, Perezpenia-Diazconti M et al (2007) Expression of PCAF, p300 and Gcn5 and more highly acetylated histone H4 in pediatric tumors. J Exp Clin Cancer Res 26(2):269–276PubMedGoogle Scholar
  6. Audrito V, Vaisitti T, Rossi D et al (2011) Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res 71(13):4473–4483. doi: 10.1158/0008-5472.CAN-10-4452 PubMedGoogle Scholar
  7. Balasubramanyam K, Swaminathan V, Ranganathan A, Kundu TK (2003) Small molecule modulators of histone acetyltransferase p300. J Biol Chem 278(21):19134–19140. doi: 10.1074/jbc.M301580200 PubMedGoogle Scholar
  8. Balasubramanyam K, Varier RA, Altaf M et al (2004) Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279(49):51163–51171. doi: 10.1074/jbc.M409024200 PubMedGoogle Scholar
  9. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381–395. doi: 10.1038/cr.2011.22 PubMedCentralPubMedGoogle Scholar
  10. Bannister AJ, Zegerman P, Partridge JF et al (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410(6824):120–124. doi: 10.1038/35065138 PubMedGoogle Scholar
  11. Barber MF, Michishita-Kioi E, Xi Y et al (2012) SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487(7405):114–118. doi: 10.1038/nature11043 PubMedCentralPubMedGoogle Scholar
  12. Baud MG, Haus P, Leiser T, Meyer-Almes FJ, Fuchter MJ (2013) Highly ligand efficient and selective N-2-(Thioethyl)picolinamide histone deacetylase inhibitors inspired by the natural product psammaplin A. ChemMedChem 8(1):149–156. doi: 10.1002/cmdc.201200450 PubMedGoogle Scholar
  13. Beaulieu N, Morin S, Chute IC, Robert MF, Nguyen H, MacLeod AR (2002) An essential role for DNA methyltransferase DNMT3B in cancer cell survival. J Biol Chem 277(31):28176–28181. doi: 10.1074/jbc.M204734200 PubMedGoogle Scholar
  14. Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA (2001) Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci USA 98(26):15113–15118. doi: 10.1073/pnas.261574398 PubMedCentralPubMedGoogle Scholar
  15. Belinsky SA, Grimes MJ, Picchi MA et al (2011) Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res 71(2):454–462. doi: 10.1158/0008-5472.CAN-10-3184 PubMedCentralPubMedGoogle Scholar
  16. Benedetti R, Conte M, Altucci L (2014) Targeting histone deacetylases in diseases: Where are we? Antioxid Redox Signal. doi: 10.1089/ars.2013.5776 PubMedGoogle Scholar
  17. Biel M, Kretsovali A, Karatzali E, Papamatheakis J, Giannis A (2004) Design, synthesis, and biological evaluation of a small-molecule inhibitor of the histone acetyltransferase Gcn5. Angew Chem 43(30):3974–3976. doi: 10.1002/anie.200453879 Google Scholar
  18. Bisht K, Wagner KH, Bulmer AC (2010) Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology 278(1):88–100. doi: 10.1016/j.tox.2009.11.008 PubMedGoogle Scholar
  19. Bojang P Jr, Ramos KS (2014) The promise and failures of epigenetic therapies for cancer treatment. Cancer Treat Rev 40(1):153–169. doi: 10.1016/j.ctrv.2013.05.009 PubMedGoogle Scholar
  20. Bose P, Dai Y, Grant S (2014) Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol Ther. doi: 10.1016/j.pharmthera.2014.04.004 PubMedGoogle Scholar
  21. Bouchard J, Momparler RL (1983) Incorporation of 5-Aza-2′-deoxycytidine-5′-triphosphate into DNA. Interactions with mammalian DNA polymerase alpha and DNA methylase. Mol Pharmacol 24(1):109–114PubMedGoogle Scholar
  22. Bowers EM, Yan G, Mukherjee C et al (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 17(5):471–482. doi: 10.1016/j.chembiol.2010.03.006 PubMedCentralPubMedGoogle Scholar
  23. Brueckner B, Garcia Boy R, Siedlecki P et al (2005) Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 65(14):6305–6311. doi: 10.1158/0008-5472.CAN-04-2957 PubMedGoogle Scholar
  24. Bruzzone S, Parenti MD, Grozio A et al (2013) Rejuvenating sirtuins: the rise of a new family of cancer drug targets. Curr Pharm Des 19(4):614–623PubMedCentralPubMedGoogle Scholar
  25. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21(1):103–107. doi: 10.1038/5047 PubMedGoogle Scholar
  26. Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A (2011) Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 17(12):1519–1528. doi: 10.3748/wjg.v17.i12.1519 PubMedCentralPubMedGoogle Scholar
  27. Candelaria M, Gallardo-Rincon D, Arce C et al (2007) A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 18(9):1529–1538. doi: 10.1093/annonc/mdm204 PubMedGoogle Scholar
  28. Cea M, Soncini D, Fruscione F et al (2011) Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells. PLoS ONE 6(7):e22739. doi: 10.1371/journal.pone.0022739 PubMedCentralPubMedGoogle Scholar
  29. Cen Y (2010) Sirtuins inhibitors: the approach to affinity and selectivity. Biochim Biophys Acta 1804(8):1635–1644. doi: 10.1016/j.bbapap.2009.11.010 PubMedGoogle Scholar
  30. Chaidos A, Caputo V, Gouvedenou K et al (2014) Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123(5):697–705. doi: 10.1182/blood-2013-01-478420 PubMedGoogle Scholar
  31. Challen GA, Sun D, Jeong M et al (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44(1):23–31. doi: 10.1038/ng.1009 Google Scholar
  32. Chang Y, Zhang X, Horton JR et al (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 16(3):312–317. doi: 10.1038/nsmb.1560 PubMedCentralPubMedGoogle Scholar
  33. Chen M, Shabashvili D, Nawab A et al (2012) DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer. Mol Cancer Ther 11(2):370–382. doi: 10.1158/1535-7163.MCT-11-0458 PubMedGoogle Scholar
  34. Cheng JC, Matsen CB, Gonzales FA et al (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95(5):399–409PubMedGoogle Scholar
  35. Cherblanc FL, Chapman KL, Brown R, Fuchter MJ (2013) Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat Chem Biol 9(3):136–137. doi: 10.1038/nchembio.1187 PubMedGoogle Scholar
  36. Chia K, Beamish H, Jafferi K, Gabrielli B (2010) The histone deacetylase inhibitor MGCD0103 has both deacetylase and microtubule inhibitory activity. Mol Pharmacol 78(3):436–443. doi: 10.1124/mol.110.065169 PubMedGoogle Scholar
  37. Coffey K, Blackburn TJ, Cook S et al (2012) Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS ONE 7(10):e45539. doi: 10.1371/journal.pone.0045539 PubMedCentralPubMedGoogle Scholar
  38. Collins HM, Abdelghany MK, Messmer M et al (2013) Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells. BMC Cancer 13:37. doi: 10.1186/1471-2407-13-37 PubMedCentralPubMedGoogle Scholar
  39. Conte M, Altucci L (2012) Molecular pathways: the complexity of the epigenome in cancer and recent clinical advances. Clin Cancer Res 18(20):5526–5534. doi: 10.1158/1078-0432.CCR-12-2037 PubMedGoogle Scholar
  40. Daigle SR, Olhava EJ, Therkelsen CA et al (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20(1):53–65. doi: 10.1016/j.ccr.2011.06.009 PubMedCentralPubMedGoogle Scholar
  41. Daigle SR, Olhava EJ, Therkelsen CA et al (2013) Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122(6):1017–1025. doi: 10.1182/blood-2013-04-497644 PubMedCentralPubMedGoogle Scholar
  42. Dalgliesh GL, Furge K, Greenman C et al (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463(7279):360–363. doi: 10.1038/nature08672 PubMedCentralPubMedGoogle Scholar
  43. Davis AJ, Gelmon KA, Siu LL et al (2003) Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks. Invest New Drugs 21(1):85–97PubMedGoogle Scholar
  44. Dawson MA, Prinjha RK, Dittmann A et al (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478(7370):529–533. doi: 10.1038/nature10509 PubMedCentralPubMedGoogle Scholar
  45. Dawson MA, Kouzarides T, Huntly BJ (2012) Targeting epigenetic readers in cancer. N Engl J Med 367(7):647–657. doi: 10.1056/NEJMra1112635 PubMedGoogle Scholar
  46. Dawson MA, Gudgin EJ, Horton SJ et al (2014) Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 28(2):311–320. doi: 10.1038/leu.2013.338 PubMedCentralPubMedGoogle Scholar
  47. Delmore JE, Issa GC, Lemieux ME et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6):904–917. doi: 10.1016/j.cell.2011.08.017 PubMedCentralPubMedGoogle Scholar
  48. Do GM, Kwon EY, Kim HJ et al (2008) Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem Biophys Res Commun 374(1):55–59. doi: 10.1016/j.bbrc.2008.06.113 PubMedGoogle Scholar
  49. Duvic M, Vu J (2007) Vorinostat in cutaneous T-cell lymphoma. Drugs Today 43(9):585–599. doi: 10.1358/dot.2007.43.9.1112980 PubMedGoogle Scholar
  50. El-Khoury V, Pierson S, Szwarcbart E et al (2014) Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia. Leukemia. doi: 10.1038/leu.2014.19 PubMedGoogle Scholar
  51. Ellis L, Pan Y, Smyth GK et al (2008) Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res 14(14):4500–4510. doi: 10.1158/1078-0432.CCR-07-4262 PubMedGoogle Scholar
  52. Erwin BG, Persson L, Pegg AE (1984) Differential inhibition of histone and polyamine acetylases by multisubstrate analogues. Biochemistry 23(18):4250–4255PubMedGoogle Scholar
  53. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8(4):286–298. doi: 10.1038/nrg2005 PubMedGoogle Scholar
  54. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159. doi: 10.1056/NEJMra072067 PubMedGoogle Scholar
  55. Fang XM, Sun LF, Peng JP, Dong Q, Zheng S (2003) The study of 5-Aza-2′-deoxycytidine on transcription regulation of p16/CDKN2 gene demethylation in RKO human colorectal cell line. Zhonghua yi xue za zhi 83(23):2077–2082PubMedGoogle Scholar
  56. Filippakopoulos P, Qi J, Picaud S et al (2010) Selective inhibition of BET bromodomains. Nature 468(7327):1067–1073. doi: 10.1038/nature09504 PubMedCentralPubMedGoogle Scholar
  57. Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460(7255):587–591. doi: 10.1038/nature08197 PubMedCentralPubMedGoogle Scholar
  58. Forneris F, Binda C, Vanoni MA, Mattevi A, Battaglioli E (2005) Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process. FEBS Lett 579(10):2203–2207. doi: 10.1016/j.febslet.2005.03.015 PubMedGoogle Scholar
  59. Franci G, Casalino L, Petraglia F et al (2013) The class I-specific HDAC inhibitor MS-275 modulates the differentiation potential of mouse embryonic stem cells. Biol Open 2(10):1070–1077. doi: 10.1242/bio.20135587 PubMedCentralPubMedGoogle Scholar
  60. Fredly H, Gjertsen BT, Bruserud O (2013) Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenet 5(1):12. doi: 10.1186/1868-7083-5-12 Google Scholar
  61. Furumai R, Matsuyama A, Kobashi N et al (2002) FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 62(17):4916–4921PubMedGoogle Scholar
  62. Garcia-Manero G (2012) Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol 87(7):692–701. doi: 10.1002/ajh.23264 PubMedGoogle Scholar
  63. George P, Bali P, Annavarapu S et al (2005) Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105(4):1768–1776. doi: 10.1182/blood-2004-09-3413 PubMedGoogle Scholar
  64. Gilbert J, Baker SD, Bowling MK et al (2001) A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 7(8):2292–2300PubMedGoogle Scholar
  65. Goffin J, Eisenhauer E (2002) DNA methyltransferase inhibitors-state of the art. Ann Oncol 13(11):1699–1716PubMedGoogle Scholar
  66. Gottlicher M, Minucci S, Zhu P et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978. doi: 10.1093/emboj/20.24.6969 PubMedCentralPubMedGoogle Scholar
  67. Graca I, Sousa EJ, Baptista T et al (2014) Anti-tumoral effect of the non-nucleoside DNMT inhibitor RG108 in human prostate cancer cells. Curr Pharm Des 20(11):1803–1811PubMedGoogle Scholar
  68. Grant S, Easley C, Kirkpatrick P (2007) Vorinostat. Nat Rev Drug Discov 6(1):21–22. doi: 10.1038/nrd2227 PubMedGoogle Scholar
  69. Gravina GL, Festuccia C, Marampon F et al (2010) Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation. Mol Cancer 9:305. doi: 10.1186/1476-4598-9-305 PubMedCentralPubMedGoogle Scholar
  70. Gridelli C, Rossi A, Maione P (2008) The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol 68(1):29–36. doi: 10.1016/j.critrevonc.2008.03.002 PubMedGoogle Scholar
  71. Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB (2011) Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 1215:150–160. doi: 10.1111/j.1749-6632.2010.05852.x PubMedCentralPubMedGoogle Scholar
  72. Gupta SC, Patchva S, Koh W, Aggarwal BB (2012) Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 39(3):283–299. doi: 10.1111/j.1440-1681.2011.05648.x PubMedCentralPubMedGoogle Scholar
  73. Harris WJ, Huang X, Lynch JT et al (2012) The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21(4):473–487. doi: 10.1016/j.ccr.2012.03.014 PubMedGoogle Scholar
  74. Hatziapostolou M, Iliopoulos D (2011) Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 68(10):1681–1702. doi: 10.1007/s00018-010-0624-z PubMedGoogle Scholar
  75. Helin K, Dhanak D (2013) Chromatin proteins and modifications as drug targets. Nature 502(7472):480–488. doi: 10.1038/nature12751 PubMedGoogle Scholar
  76. Heltweg B, Gatbonton T, Schuler AD et al (2006) Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 66(8):4368–4377. doi: 10.1158/0008-5472.CAN-05-3617 PubMedGoogle Scholar
  77. Herranz MC, Sanchez-Navarro JA, Aparicio F, Pallas V (2005) Simultaneous detection of six stone fruit viruses by non-isotopic molecular hybridization using a unique riboprobe or ‘polyprobe’. J Virol Methods 124(1–2):49–55. doi: 10.1016/j.jviromet.2004.11.003 PubMedGoogle Scholar
  78. Herranz M, Martin-Caballero J, Fraga MF et al (2006) The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. Blood 107(3):1174–1177. doi: 10.1182/blood-2005-05-2033 PubMedGoogle Scholar
  79. Hirao M, Posakony J, Nelson M et al (2003) Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast. J Biol Chem 278(52):52773–52782. doi: 10.1074/jbc.M308966200 PubMedGoogle Scholar
  80. Hojfeldt JW, Agger K, Helin K (2013) Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discovery 12(12):917–930. doi: 10.1038/nrd4154 Google Scholar
  81. Howitz KT, Bitterman KJ, Cohen HY et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. doi: 10.1038/nature01960 PubMedGoogle Scholar
  82. Huang H, Zhang J, Shen W et al (2007) Solution structure of the second bromodomain of Brd2 and its specific interaction with acetylated histone tails. BMC Struct Biol 7:57. doi: 10.1186/1472-6807-7-57 PubMedCentralPubMedGoogle Scholar
  83. Isham CR, Tibodeau JD, Jin W, Xu R, Timm MM, Bible KC (2007) Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. Blood 109(6):2579–2588. doi: 10.1182/blood-2006-07-027326 PubMedCentralPubMedGoogle Scholar
  84. Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303. doi: 10.1126/science.1210597 PubMedCentralPubMedGoogle Scholar
  85. Jair KW, Bachman KE, Suzuki H et al (2006) De novo CpG island methylation in human cancer cells. Cancer Res 66(2):682–692. doi: 10.1158/0008-5472.CAN-05-1980 PubMedGoogle Scholar
  86. Jin SG, Jiang Y, Qiu R et al (2011) 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 71(24):7360–7365. doi: 10.1158/0008-5472.CAN-11-2023 PubMedCentralPubMedGoogle Scholar
  87. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. doi: 10.1016/j.cell.2007.01.029 PubMedCentralPubMedGoogle Scholar
  88. Jung-Hynes B, Ahmad N (2009) SIRT1 controls circadian clock circuitry and promotes cell survival: a connection with age-related neoplasms. FASEB J 23(9):2803–2809. doi: 10.1096/fj.09-129148 PubMedCentralPubMedGoogle Scholar
  89. Juttermann R, Li E, Jaenisch R (1994) Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA 91(25):11797–11801PubMedCentralPubMedGoogle Scholar
  90. Kadia TM, Jabbour E, Kantarjian H (2011) Failure of hypomethylating agent-based therapy in myelodysplastic syndromes. Semin Oncol 38(5):682–692. doi: 10.1053/j.seminoncol.2011.04.011 PubMedCentralPubMedGoogle Scholar
  91. Karthik S, Sankar R, Varunkumar K, Ravikumar V (2014) Romidepsin induces cell cycle arrest, apoptosis, histone hyperacetylation and reduces matrix metalloproteinases 2 and 9 expression in bortezomib sensitized non-small cell lung cancer cells. Biomed Pharmacother 68(3):327–334. doi: 10.1016/j.biopha.2014.01.002 PubMedGoogle Scholar
  92. Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94. doi: 10.1038/icb.2011.100 PubMedGoogle Scholar
  93. Kimura A, Matsubara K, Horikoshi M (2005) A decade of histone acetylation: marking eukaryotic chromosomes with specific codes. J Biochem 138(6):647–662. doi: 10.1093/jb/mvi184 PubMedGoogle Scholar
  94. Klein CJ, Botuyan MV, Wu Y et al (2011) Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 43(6):595–600. doi: 10.1038/ng.830 PubMedCentralPubMedGoogle Scholar
  95. Klisovic RB, Stock W, Cataland S et al (2008) A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia. Clin Cancer Res 14(8):2444–2449. doi: 10.1158/1078-0432.CCR-07-1320 PubMedGoogle Scholar
  96. Knutson SK, Warholic NM, Wigle TJ et al (2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci USA 110(19):7922–7927. doi: 10.1073/pnas.1303800110 PubMedCentralPubMedGoogle Scholar
  97. Kooistra SM, Helin K (2012) Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 13(5):297–311. doi: 10.1038/nrm3327 PubMedGoogle Scholar
  98. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705. doi: 10.1016/j.cell.2007.02.005 PubMedGoogle Scholar
  99. Kruidenier L, Chung CW, Cheng Z et al (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488(7411):404–408. doi: 10.1038/nature11262 PubMedGoogle Scholar
  100. Kubicek S, O’Sullivan RJ, August EM et al (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25(3):473–481. doi: 10.1016/j.molcel.2007.01.017 PubMedGoogle Scholar
  101. Kurundkar D, Srivastava RK, Chaudhary SC et al (2013) Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model. Toxicol Appl Pharmacol 266(2):233–244. doi: 10.1016/j.taap.2012.11.002 PubMedCentralPubMedGoogle Scholar
  102. Kuttan R, Sudheeran PC, Josph CD (1987) Turmeric and curcumin as topical agents in cancer therapy. Tumori 73(1):29–31PubMedGoogle Scholar
  103. Lau OD, Kundu TK, Soccio RE et al (2000) HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell 5(3):589–595PubMedGoogle Scholar
  104. Lee BH, Yegnasubramanian S, Lin X, Nelson WG (2005a) Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem 280(49):40749–40756. doi: 10.1074/jbc.M505593200 PubMedCentralPubMedGoogle Scholar
  105. Lee WJ, Shim JY, Zhu BT (2005b) Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol 68(4):1018–1030. doi: 10.1124/mol.104.008367 PubMedGoogle Scholar
  106. Lee JH, Choy ML, Ngo L, Foster SS, Marks PA (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA 107(33):14639–14644. doi: 10.1073/pnas.1008522107 PubMedCentralPubMedGoogle Scholar
  107. Lee JH, Choy ML, Ngo L, Venta-Perez G, Marks PA (2011) Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors. Proc Natl Acad Sci USA 108(49):19629–19634. doi: 10.1073/pnas.1117544108 PubMedCentralPubMedGoogle Scholar
  108. Leone G, Teofili L, Voso MT, Lubbert M (2002) DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica 87(12):1324–1341PubMedGoogle Scholar
  109. Ley TJ, Ding L, Walter MJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363(25):2424–2433. doi: 10.1056/NEJMoa1005143 PubMedCentralPubMedGoogle Scholar
  110. Liu F, Chen X, Allali-Hassani A et al (2009) Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 52(24):7950–7953. doi: 10.1021/Jm901543m PubMedCentralPubMedGoogle Scholar
  111. Liu F, Chen X, Allali-Hassani A et al (2010) Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. J Med Chem 53(15):5844–5857. doi: 10.1021/jm100478y PubMedCentralPubMedGoogle Scholar
  112. Liu F, Barsyte-Lovejoy D, Li F et al (2013) Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem 56(21):8931–8942. doi: 10.1021/jm401480r PubMedGoogle Scholar
  113. Maes T, Tirapu I, Mascaro C et al (2013) Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia. J Clin Oncol 31(15):e13543Google Scholar
  114. Mai A (2007) The therapeutic uses of chromatin-modifying agents. Expert Opin Ther Targets 11(6):835–851. doi: 10.1517/14728222.11.6.835 PubMedGoogle Scholar
  115. Mai A, Altucci L (2009) Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead. Int J Biochem Cell Biol 41(1):199–213. doi: 10.1016/j.biocel.2008.08.020 PubMedGoogle Scholar
  116. Mantelingu K, Kishore AH, Balasubramanyam K et al (2007) Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: probed by surface-enhanced Raman spectroscopy. J Phys Chem B 111(17):4527–4534. doi: 10.1021/jp067655s PubMedGoogle Scholar
  117. Marcu MG, Jung YJ, Lee S et al (2006) Curcumin is an inhibitor of p300 histone acetylatransferase. Med Chem 2(2):169–174PubMedGoogle Scholar
  118. Marks PW (2012) Decitabine for acute myeloid leukemia. Expert Rev Anticancer Ther 12(3):299–305. doi: 10.1586/era.11.207 PubMedGoogle Scholar
  119. Marks PA, Richon VM, Breslow R, Rifkind RA (2001) Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 13(6):477–483PubMedGoogle Scholar
  120. McCabe MT, Ott HM, Ganji G et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492(7427):108–112. doi: 10.1038/nature11606 PubMedGoogle Scholar
  121. McDonough MA, Loenarz C, Chowdhury R, Clifton IJ, Schofield CJ (2010) Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol 20(6):659–672. doi: 10.1016/j.sbi.2010.08.006 PubMedGoogle Scholar
  122. McGeary RP, Bennett AJ, Tran QB, Cosgrove KL, Ross BP (2008) Suramin: clinical uses and structure-activity relationships. Mini Rev Med Chem 8(13):1384–1394PubMedGoogle Scholar
  123. Meng F, Sun G, Zhong M, Yu Y, Brewer MA (2013) Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2′-deoxycytidine on ovarian cancer. Br J Cancer 108(3):579–586. doi: 10.1038/bjc.2013.10 PubMedCentralPubMedGoogle Scholar
  124. Mertz JA, Conery AR, Bryant BM et al (2011) Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA 108(40):16669–16674. doi: 10.1073/pnas.1108190108 PubMedCentralPubMedGoogle Scholar
  125. Milne JC, Lambert PD, Schenk S et al (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450(7170):712–716. doi: 10.1038/nature06261 PubMedCentralPubMedGoogle Scholar
  126. Mirguet O, Gosmini R, Toum J et al (2013) Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem 56(19):7501–7515. doi: 10.1021/jm401088k PubMedGoogle Scholar
  127. Momparler RL, Bovenzi V (2000) DNA methylation and cancer. J Cell Physiol 183(2):145–154. doi: 10.1002/(SICI)1097-4652(200005)183:2<145::AID-JCP1>3.0.CO;2-V PubMedGoogle Scholar
  128. Mummaneni P, Shord SS (2014) Epigenetics and oncology. Pharmacotherapy 34(5):495–505. doi: 10.1002/phar.1408 PubMedGoogle Scholar
  129. Muraoka M, Konishi M, Kikuchi-Yanoshita R et al (1996) p300 gene alterations in colorectal and gastric carcinomas. Oncogene 12(7):1565–1569PubMedGoogle Scholar
  130. Nakagawa H, Hasumi K, Woo JT, Nagai K, Wachi M (2004) Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (−)-epigallocatechin gallate. Carcinogenesis 25(9):1567–1574. doi: 10.1093/carcin/bgh168 PubMedGoogle Scholar
  131. Nakamura K, Aizawa K, Nakabayashi K et al (2013) DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis. PLoS ONE 8(1):e54036. doi: 10.1371/journal.pone.0054036 PubMedCentralPubMedGoogle Scholar
  132. Napper AD, Hixon J, McDonagh T et al (2005) Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 48(25):8045–8054. doi: 10.1021/jm050522v PubMedGoogle Scholar
  133. Nebbioso A, Pereira R, Khanwalkar H et al (2011) Death receptor pathway activation and increase of ROS production by the triple epigenetic inhibitor UVI5008. Mol Cancer Ther 10(12):2394–2404. doi: 10.1158/1535-7163.MCT-11-0525 PubMedGoogle Scholar
  134. Nebbioso A, Carafa V, Benedetti R, Altucci L (2012) Trials with ‘epigenetic’ drugs: an update. Mol Oncol 6(6):657–682. doi: 10.1016/j.molonc.2012.09.004 PubMedGoogle Scholar
  135. Oike T, Ogiwara H, Torikai K, Nakano T, Yokota J, Kohno T (2012) Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining. Int J Radiat Oncol Biol Phys 84(3):815–821. doi: 10.1016/j.ijrobp.2012.01.017 PubMedGoogle Scholar
  136. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257PubMedGoogle Scholar
  137. Oki Y, Buglio D, Fanale M et al (2013) Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res 19(24):6882–6890. doi: 10.1158/1078-0432.CCR-13-1906 PubMedGoogle Scholar
  138. Olsen EA, Kim YH, Kuzel TM et al (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25(21):3109–3115. doi: 10.1200/JCO.2006.10.2434 PubMedGoogle Scholar
  139. Outeiro TF, Kontopoulos E, Altmann SM et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837):516–519. doi: 10.1126/science.1143780 PubMedGoogle Scholar
  140. Pacholec M, Bleasdale JE, Chrunyk B et al (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285(11):8340–8351. doi: 10.1074/jbc.M109.088682 PubMedCentralPubMedGoogle Scholar
  141. Patutina OA, Mironova NL, Vlassov VV, Zenkova MA (2009) New approaches for cancer treatment: antitumor drugs based on gene-targeted nucleic acids. Acta Nat 1(2):44–60Google Scholar
  142. Perego P, Zuco V, Gatti L, Zunino F (2012) Sensitization of tumor cells by targeting histone deacetylases. Biochem Pharmacol 83(8):987–994. doi: 10.1016/j.bcp.2011.11.010 PubMedGoogle Scholar
  143. Pfeifer GP, Kadam S, Jin SG (2013) 5-hydroxymethylcytosine and its potential roles in development and cancer. Epigenetics Chromatin 6(1):10. doi: 10.1186/1756-8935-6-10 PubMedCentralPubMedGoogle Scholar
  144. Pili R, Salumbides B, Zhao M et al (2012) Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Br J Cancer 106(1):77–84. doi: 10.1038/bjc.2011.527 PubMedCentralPubMedGoogle Scholar
  145. Pina IC, Gautschi JT, Wang GY et al (2003) Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J Org Chem 68(10):3866–3873. doi: 10.1021/jo034248t PubMedGoogle Scholar
  146. Qian DZ, Kachhap SK, Collis SJ et al (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66(17):8814–8821. doi: 10.1158/0008-5472.CAN-05-4598 PubMedGoogle Scholar
  147. Ragno R, Simeoni S, Castellano S et al (2007) Small molecule inhibitors of histone arginine methyltransferases: homology modeling, molecular docking, binding mode analysis, and biological evaluations. J Med Chem 50(6):1241–1253. doi: 10.1021/jm061213n PubMedGoogle Scholar
  148. Rhodes LV, Nitschke AM, Segar HC et al (2012) The histone deacetylase inhibitor trichostatin A alters microRNA expression profiles in apoptosis-resistant breast cancer cells. Oncol Rep 27(1):10–16. doi: 10.3892/or.2011.1488 PubMedCentralPubMedGoogle Scholar
  149. Richon VM (2008) A new path to the cancer epigenome. Nat Biotechnol 26(6):655–656. doi: 10.1038/nbt0608-655 PubMedGoogle Scholar
  150. Richon VM, Emiliani S, Verdin E et al (1998) A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA 95(6):3003–3007PubMedCentralPubMedGoogle Scholar
  151. Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20(24):3139–3155. doi: 10.1038/sj.onc.1204341 PubMedGoogle Scholar
  152. Robertson KD, Uzvolgyi E, Liang G et al (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27(11):2291–2298PubMedCentralPubMedGoogle Scholar
  153. Rocha-Gonzalez HI, Ambriz-Tututi M, Granados-Soto V (2008) Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 14(3):234–247. doi: 10.1111/j.1755-5949.2008.00045.x PubMedGoogle Scholar
  154. Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17(3):330–339. doi: 10.1038/nm.2305 PubMedGoogle Scholar
  155. Rosato R, Hock S, Dent P, Dai Y, Grant S (2012) LBH-589 (panobinostat) potentiates fludarabine anti-leukemic activity through a JNK- and XIAP-dependent mechanism. Leuk Res 36(4):491–498. doi: 10.1016/j.leukres.2011.10.020 PubMedCentralPubMedGoogle Scholar
  156. Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8(12):983–994. doi: 10.1038/nrm2298 PubMedGoogle Scholar
  157. Ryan QC, Headlee D, Acharya M et al (2005) Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23(17):3912–3922. doi: 10.1200/JCO.2005.02.188 PubMedGoogle Scholar
  158. Sagar V, Zheng W, Thompson PR, Cole PA (2004) Bisubstrate analogue structure-activity relationships for p300 histone acetyltransferase inhibitors. Bioorg Med Chem 12(12):3383–3390. doi: 10.1016/j.bmc.2004.03.070 PubMedGoogle Scholar
  159. Sakane C, Okitsu T, Wada A, Sagami H, Shidoji Y (2014) Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives. Biochem Biophys Res Commun 444(1):24–29. doi: 10.1016/j.bbrc.2013.12.144 PubMedGoogle Scholar
  160. Savickiene J, Treigyte G, Jazdauskaite A, Borutinskaite VV, Navakauskiene R (2012) DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors cooperate to enhance NB4 cell differentiation and E-cadherin re-expression by chromatin remodelling. Cell Biol Int 36(11):1067–1078. doi: 10.1042/CBI20110649 PubMedGoogle Scholar
  161. Schaefer M, Lyko F (2010) Solving the Dnmt2 enigma. Chromosoma 119(1):35–40. doi: 10.1007/s00412-009-0240-6 PubMedGoogle Scholar
  162. Schaefer M, Pollex T, Hanna K, Tuorto F, Meusburger M, Helm M, Lyko F (2010) RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev 24(15):1590–1595. doi:  10.1101/gad.586710
  163. Schuetz A, Min J, Antoshenko T et al (2007) Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure 15(3):377–389. doi: 10.1016/j.str.2007.02.002 PubMedGoogle Scholar
  164. Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E et al (2003) Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin Cancer Res 9(5):1596–1603PubMedGoogle Scholar
  165. Shukla Y, Singh R (2011) Resveratrol and cellular mechanisms of cancer prevention. Ann N Y Acad Sci 1215:1–8. doi: 10.1111/j.1749-6632.2010.05870.x PubMedGoogle Scholar
  166. Sikandar S, Dizon D, Shen X, Li Z, Besterman J, Lipkin SM (2010) The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling. Oncotarget 1(7):596–605PubMedCentralPubMedGoogle Scholar
  167. Silvestri L, Ballante F, Mai A, Marshall GR, Ragno R (2012) Histone deacetylase inhibitors: structure-based modeling and isoform-selectivity prediction. J Chem Inf Model 52(8):2215–2235. doi: 10.1021/ci300160y PubMedGoogle Scholar
  168. Skliris GP, Munot K, Bell SM et al (2003) Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol 201(2):213–220. doi: 10.1002/path.1436 PubMedGoogle Scholar
  169. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789(1):45–57. doi: 10.1016/j.bbagrm.2008.06.005 PubMedCentralPubMedGoogle Scholar
  170. Song S, Yu B, Wei Y, Wientjes MG, Au JL (2004) Low-dose suramin enhanced paclitaxel activity in chemotherapy-naive and paclitaxel-pretreated human breast xenograft tumors. Clin Cancer Res 10(18 Pt 1):6058–6065. doi: 10.1158/1078-0432.CCR-04-0595 PubMedGoogle Scholar
  171. Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M (2009) The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4(10):1568–1582. doi: 10.1002/cmdc.200900301 PubMedGoogle Scholar
  172. Sroczynska P, Cruickshank VA, Bukowski JP et al (2014) shRNA screening identifies JMJD1C as being required for leukemia maintenance. Blood 123(12):1870–1882. doi: 10.1182/blood-2013-08-522094 PubMedGoogle Scholar
  173. Stewart DJ, Donehower RC, Eisenhauer EA et al (2003) A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. Ann Oncol 14(5):766–774PubMedGoogle Scholar
  174. Stimson L, Rowlands MG, Newbatt YM et al (2005) Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Mol Cancer Ther 4(10):1521–1532. doi: 10.1158/1535-7163.MCT-05-0135 PubMedGoogle Scholar
  175. Stolfa DA, Stefanachi A, Gajer JM et al (2012) Design, synthesis, and biological evaluation of 2-aminobenzanilide derivatives as potent and selective HDAC inhibitors. ChemMedChem 7(7):1256–1266. doi: 10.1002/cmdc.201200193 PubMedGoogle Scholar
  176. Suzuki H, Gabrielson E, Chen W et al (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31(2):141–149. doi: 10.1038/ng892 PubMedGoogle Scholar
  177. Sweis RF, Pliushchev M, Brown PJ et al (2014) Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett 5(2):205–209. doi: 10.1021/ml400496h PubMedGoogle Scholar
  178. Tan J, Yang X, Zhuang L et al (2007) Pharmacologic disruption of polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21(9):1050–1063. doi: 10.1101/gad.1524107 PubMedCentralPubMedGoogle Scholar
  179. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14(11):1025–1040. doi: 10.1038/nsmb1338 PubMedGoogle Scholar
  180. Terao Y, Nishida J, Horiuchi S et al (2001) Sodium butyrate induces growth arrest and senescence-like phenotypes in gynecologic cancer cells. Int J Cancer J Int Du Cancer 94(2):257–267Google Scholar
  181. Timmers S, Auwerx J, Schrauwen P (2012) The journey of resveratrol from yeast to human. Aging 4(3):146–158PubMedCentralPubMedGoogle Scholar
  182. Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K (1976) A new antifungal antibiotic, trichostatin. J Antibiot 29(1):1–6PubMedGoogle Scholar
  183. Ueda R, Suzuki T, Mino K et al (2009) Identification of cell-active lysine specific demethylase 1-selective inhibitors. J Am Chem Soc 131(48):17536–17537. doi: 10.1021/ja907055q PubMedGoogle Scholar
  184. van Haaften G, Dalgliesh GL, Davies H et al (2009) Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 41(5):521–523. doi: 10.1038/ng.349 PubMedCentralPubMedGoogle Scholar
  185. Vannini A, Volpari C, Filocamo G et al (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 101(42):15064–15069. doi: 10.1073/pnas.0404603101 PubMedCentralPubMedGoogle Scholar
  186. Villalba JM, Alcain FJ (2012) Sirtuin activators and inhibitors. BioFactors 38(5):349–359. doi: 10.1002/biof.1032 PubMedCentralPubMedGoogle Scholar
  187. Villar-Garea A, Esteller M (2003) DNA demethylating agents and chromatin-remodelling drugs: which, how and why? Curr Drug Metab 4(1):11–31PubMedGoogle Scholar
  188. Walter MJ, Ding L, Shen D et al (2011) Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25(7):1153–1158. doi: 10.1038/leu.2011.44 PubMedCentralPubMedGoogle Scholar
  189. Wang H, Yang YJ, Qian HY, Zhang Q, Xu H, Li JJ (2012) Resveratrol in cardiovascular disease: what is known from current research? Heart Fail Rev 17(3):437–448. doi: 10.1007/s10741-011-9260-4 PubMedGoogle Scholar
  190. Whetstine JR, Nottke A, Lan F et al (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125(3):467–481. doi: 10.1016/j.cell.2006.03.028 PubMedGoogle Scholar
  191. Xu S, Ren J, Chen HB et al (2014) Cytostatic and apoptotic effects of DNMT and HDAC inhibitors in endometrial cancer cells. Curr Pharm Des 20(11):1881–1887PubMedGoogle Scholar
  192. Yang Q, Wang B, Zang W et al (2013) Resveratrol inhibits the growth of gastric cancer by inducing G1 phase arrest and senescence in a Sirt1-dependent manner. PLoS ONE 8(11):e70627. doi: 10.1371/journal.pone.0070627 PubMedCentralPubMedGoogle Scholar
  193. Zuber J, Shi J, Wang E et al (2011) RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478(7370):524–528. doi: 10.1038/nature10334 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Antonella Di Costanzo
    • 1
  • Nunzio Del Gaudio
    • 1
  • Antimo Migliaccio
    • 1
  • Lucia Altucci
    • 1
  1. 1.Dipartimento di Biochimica, Biofisica e Patologia GeneraleSeconda Università degli Studi di NapoliNaplesItaly

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