Epigenetic Targeting Therapies to Overcome Chemotherapy Resistance

Chapter
Part of the Advances in Experimental Medicine and Biology book series (volume 754)

Abstract

It is now well established that epigenetic aberrations occur early in malignant transformation, raising the possibility of identifying chemopreventive compounds or reliable diagnostic screening using epigenetic biomarkers. Combinatorial therapies effective for the reexpression of tumor suppressors, facilitating resensitization to conventional chemotherapies, hold great promise for the future therapy of cancer. This approach may also perturb cancer stem cells and thus represent an effective means for managing a number of solid tumors. We believe that in the near future, anticancer drug regimens will routinely include epigenetic therapies, possibly in conjunction with inhibitors of “stemness” signal pathways, to effectively reduce the devastating occurrence of cancer chemotherapy resistance.

Notes

Acknowledgments

The authors affirm no conflict of interest regarding any of the content of this manuscript. The authors gratefully acknowledge grant support from the United States National Institutes of Health, National Cancer Institute awards CA085289, CA113001, the Ovarian Cancer Research Foundation [PPD/IU/01.2011] (New York, NY), the American Cancer Society Indiana University Research Grant #84-002-25, the Walther Cancer Foundation (Indianapolis, IN), and Ovar’coming Together, Inc. (Indianapolis, IN).

References

  1. 1.
    Gralow J, Ozols RF, Bajorin DF, Cheson BD, Sandler HM, Winer EP, Bonner J, Demetri GD, Curran W Jr, Ganz PA, Kramer BS, Kris MG, Markman M, Mayer RJ, Raghavan D, Ramsey S, Reaman GH, Sawaya R, Schuchter LM, Sweetenham JW, Vahdat LT, Davidson NE, Schilsky RL, Lichter AS (2008) Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 26(2):313–325PubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300PubMedGoogle Scholar
  3. 3.
    Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292PubMedGoogle Scholar
  4. 4.
    Raguz S, Yague E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99(3):387–391PubMedGoogle Scholar
  5. 5.
    Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441–1454PubMedGoogle Scholar
  6. 6.
    Balch C, Huang TH, Brown R, Nephew KP (2004) The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol 191(5):1552–1572PubMedGoogle Scholar
  7. 7.
    Barton CA, Clark SJ, Hacker NF, O’Brien PM (2008) Epigenetic markers of ovarian cancer. Adv Exp Med Biol 622:35–51PubMedGoogle Scholar
  8. 8.
    Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692PubMedGoogle Scholar
  9. 9.
    Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159PubMedGoogle Scholar
  10. 10.
    Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17(3):330–339PubMedGoogle Scholar
  11. 11.
    Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H (2007) Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res 67(21):10117–10122PubMedGoogle Scholar
  12. 12.
    Wiley A, Katsaros D, Chen H, Rigault de la Longrais IA, Beeghly A, Puopolo M, Singal R, Zhang Y, Amoako A, Zelterman D, Yu H (2006) Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential. Cancer 107(2):299–308PubMedGoogle Scholar
  13. 13.
    Daley GQ (2008) Common themes of dedifferentiation in somatic cell reprogramming and cancer. Cold Spring Harb Symp Quant Biol 73:171–174PubMedGoogle Scholar
  14. 14.
    Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7(6):505–512PubMedGoogle Scholar
  15. 15.
    Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284PubMedGoogle Scholar
  16. 16.
    Jordan CT (2009) Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4(3):203–205PubMedGoogle Scholar
  17. 17.
    Von Hoff DD, Slavik M, Muggia FM (1976) 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 85(2):237–245Google Scholar
  18. 18.
    Delva L, Zelent A, Naoe T, Fenaux P, Waxman S, Degos L, Chomienne C (2007) Meeting report: the 11th International Conference on Differentiation Therapy and Innovative Therapeutics in Oncology. Cancer Res 67(22):10635–10637PubMedGoogle Scholar
  19. 19.
    Ma WW, Adjei AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59(2):111–137PubMedGoogle Scholar
  20. 20.
    Vincent A, Van Seuningen I (2009) Epigenetics, stem cells and epithelial cell fate. Differentiation 78(2–3):99–107PubMedGoogle Scholar
  21. 21.
    Scaffidi P, Misteli T (2010) Cancer epigenetics: from disruption of differentiation programs to the emergence of cancer stem cells. Cold Spring Harb Symp Quant Biol 75:251–258PubMedGoogle Scholar
  22. 22.
    Lotem J, Sachs L (2006) Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene 25(59):7663–7672PubMedGoogle Scholar
  23. 23.
    Djuric U, Ellis J (2010) Epigenetics of induced pluripotency, the seven-headed dragon. Stem Cell Res Ther 1(1):3PubMedGoogle Scholar
  24. 24.
    Hochedlinger K, Plath K (2009) Epigenetic reprogramming and induced pluripotency. Development 136(4):509–523PubMedGoogle Scholar
  25. 25.
    Costa FF, Seftor EA, Bischof JM, Kirschmann DA, Strizzi L, Arndt K, de Fatima Bonaldo M, Soares MB, Hendrix MJ (2009) Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics 1(2):387–398PubMedGoogle Scholar
  26. 26.
    Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit LM (2007) Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7(4):246–255PubMedGoogle Scholar
  27. 27.
    Goldin A, Sandberg JS, Henderson ES, Newman JW, Frei E III, Holland JF (1971) The chemotherapy of human and animal acute leukemia. Cancer Chemother Pharmacol 55(4):309–505Google Scholar
  28. 28.
    Ney PA, D’Andrea AD (2000) Friend erythroleukemia revisited. Blood 96(12):3675–3680PubMedGoogle Scholar
  29. 29.
    Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20(1):85–93PubMedGoogle Scholar
  30. 30.
    Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27(32):5459–5468PubMedGoogle Scholar
  31. 31.
    Yang X, Lay F, Han H, Jones PA (2010) Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci 31(11):536–546PubMedGoogle Scholar
  32. 32.
    Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res 13(6):1634–1637PubMedGoogle Scholar
  33. 33.
    Ewald B, Sampath D, Plunkett W (2008) Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27(50):6522–6537PubMedGoogle Scholar
  34. 34.
    Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5(1):37–50PubMedGoogle Scholar
  35. 35.
    Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H (2008) Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 112(11):2341–2351PubMedGoogle Scholar
  36. 36.
    Piskala A, Sorm F (1964) Nucleic acids components and the analogues. LI. Synthesis of 1-glycosyl derivatives of 5-azauracil and 5-azacytosine. Collect Czech Chem Commun 29:2060–2076Google Scholar
  37. 37.
    Shutt RH, Krueger RG (1972) The effect of actinomycin D and 5-azacytidine on macromolecular synthesis in murine myeloma tumor cells. J Immunol 108(3):819–830PubMedGoogle Scholar
  38. 38.
    Takai N, Kawamata N, Walsh CS, Gery S, Desmond JC, Whittaker S, Said JW, Popoviciu LM, Jones PA, Miyakawa I, Koeffler HP (2005) Discovery of epigenetically masked tumor suppressor genes in endometrial cancer. Mol Cancer Res 3(5):261–269PubMedGoogle Scholar
  39. 39.
    Sasaki M, Kaneuchi M, Fujimoto S, Tanaka Y, Dahiya R (2003) Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. Mol Cell Endocrinol 202(1–2):201–207PubMedGoogle Scholar
  40. 40.
    Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G, Jones PA (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res 62(22):6456–6461PubMedGoogle Scholar
  41. 41.
    Abbosh PH, Montgomery JS, Starkey JA, Novotny M, Zuhowski EG, Egorin MJ, Moseman AP, Golas A, Brannon KM, Balch C, Huang TH, Nephew KP (2006) Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res 66(11):5582–5591PubMedGoogle Scholar
  42. 42.
    Vesely J (1982) Synergistic effect of cis-dichlorodiammineplatinum and 5-aza-2′-deoxycytidine on mouse leukemic cells in vivo and in vitro. Int J Cancer 29(1):81–85PubMedGoogle Scholar
  43. 43.
    Taylor SM, Jones PA (1982) Mechanism of action of eukaryotic DNA methyltransferase. Use of 5-azacytosine-containing DNA. J Mol Biol 162(3):679–692PubMedGoogle Scholar
  44. 44.
    Nakahara Y, Northcott PA, Li M, Kongkham PN, Smith C, Yan H, Croul S, Ra YS, Eberhart C, Huang A, Bigner D, Grajkowska W, Van Meter T, Rutka JT, Taylor MD (2010) Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma. Neoplasia 12(1):20–27PubMedGoogle Scholar
  45. 45.
    Mahesh S, Saxena A, Qiu X, Perez-Soler R, Zou Y (2010) Intratracheally administered 5-azacytidine is effective against orthotopic human lung cancer xenograft models and devoid of important systemic toxicity. Clin Lung Cancer 11(6):405–411PubMedGoogle Scholar
  46. 46.
    Walker C, Shay JW (1984) 5-Azacytidine induced myogenesis in a differentiation defective cell line. Differentiation 25(3):259–263PubMedGoogle Scholar
  47. 47.
    Liu L, Harrington M, Jones PA (1986) Characterization of myogenic cell lines derived by 5-azacytidine treatment. Dev Biol 117(2):331–336PubMedGoogle Scholar
  48. 48.
    Hustad CM, Jones PA (1991) Effect of myogenic determination on tumorigenicity of chemically transformed 10T1/2 cells. Mol Carcinog 4(2):153–161PubMedGoogle Scholar
  49. 49.
    Schneider-Stock R, Diab-Assef M, Rohrbeck A, Foltzer-Jourdainne C, Boltze C, Hartig R, Schonfeld P, Roessner A, Gali-Muhtasib H (2005) 5-Aza-cytidine is a potent inhibitor of DNA methyltransferase 3a and induces apoptosis in HCT-116 colon cancer cells via Gadd45- and p53-dependent mechanisms. J Pharmacol Exp Ther 312(2):525–536PubMedGoogle Scholar
  50. 50.
    Wang XM, Wang X, Li J, Evers BM (1998) Effects of 5-azacytidine and butyrate on differentiation and apoptosis of hepatic cancer cell lines. Ann Surg 227(6):922–931PubMedGoogle Scholar
  51. 51.
    Burrows JF, Chanduloy S, McIlhatton MA, Nagar H, Yeates K, Donaghy P, Price J, Godwin AK, Johnston PG, Russell SE (2003) Altered expression of the septin gene, SEPT9, in ovarian neoplasia. J Pathol 201(4):581–588PubMedGoogle Scholar
  52. 52.
    Balch C, Montgomery JS, Paik HI, Kim S, Huang TH, Nephew KP (2005) New anti-cancer strategies: epigenetic therapies and biomarkers. Front Biosci 10:1897–1931PubMedGoogle Scholar
  53. 53.
    Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2′-deoxycytidine (decitabine). Semin Oncol 32(5):443–451PubMedGoogle Scholar
  54. 54.
    Wilson VL, Jones PA, Momparler RL (1983) Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2′-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res 43(8):3493–3496PubMedGoogle Scholar
  55. 55.
    Momparler RL, Bouchard J, Samson J (1985) Induction of differentiation and inhibition of DNA methylation in HL-60 myeloid leukemic cells by 5-AZA-2′-deoxycytidine. Leuk Res 9(11):1361–1366PubMedGoogle Scholar
  56. 56.
    Limonta M, Colombo T, Damia G, Catapano CV, Conter V, Gervasoni M, Masera G, Liso V, Specchia G, Giudici G et al (1993) Cytotoxic activity and mechanism of action of 5-Aza-2′-deoxycytidine in human CML cells. Leuk Res 17(11):977–982PubMedGoogle Scholar
  57. 57.
    Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5′ CpG island methylation. Cancer Res 59(14):3352–3356PubMedGoogle Scholar
  58. 58.
    Schnekenburger M, Grandjenette C, Ghelfi J, Karius T, Foliguet B, Dicato M, Diederich M (2011) Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy. Biochem Pharmacol 81(3):364–378PubMedGoogle Scholar
  59. 59.
    Obata T, Toyota M, Satoh A, Sasaki Y, Ogi K, Akino K, Suzuki H, Murai M, Kikuchi T, Mita H, Itoh F, Issa JP, Tokino T, Imai K (2003) Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9(17):6410–6418PubMedGoogle Scholar
  60. 60.
    Alcazar O, Achberger S, Aldrich W, Hu Z, Negrotto S, Saunthararajah Y, Triozzi P (2012) Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J Cancer 131(1):18–29PubMedGoogle Scholar
  61. 61.
    Chen W, Gao N, Shen Y, Cen JN (2010) Hypermethylation downregulates Runx3 gene expression and its restoration suppresses gastric epithelial cell growth by inducing p27 and caspase3 in human gastric cancer. J Gastroenterol Hepatol 25(4):823–831PubMedGoogle Scholar
  62. 62.
    Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C, Wang YC (2010) SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res 70(2):543–551PubMedGoogle Scholar
  63. 63.
    Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J (2010) miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis 31(5):766–776PubMedGoogle Scholar
  64. 64.
    Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y (2010) Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. Carcinogenesis 31(5):777–784PubMedGoogle Scholar
  65. 65.
    Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, Garcia JM, Munoz A, Esteller M, Gonzalez-Sancho JM (2006) Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25(29):4116–4121PubMedGoogle Scholar
  66. 66.
    Chuang JC, Warner SL, Vollmer D, Vankayalapati H, Redkar S, Bearss DJ, Qiu X, Yoo CB, Jones PA (2010) S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther 9(5):1443–1450PubMedGoogle Scholar
  67. 67.
    Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, Redkar S, Jones PA (2007) Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 67(13):6400–6408PubMedGoogle Scholar
  68. 68.
    Brueckner B, Rius M, Markelova MR, Fichtner I, Hals PA, Sandvold ML, Lyko F (2010) Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol Cancer Ther 9(5):1256–1264PubMedGoogle Scholar
  69. 69.
    Leu YW, Rahmatpanah F, Shi H, Wei SH, Liu JC, Yan PS, Huang TH (2003) Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Res 63(19):6110–6115PubMedGoogle Scholar
  70. 70.
    Balch C, Yan P, Craft T, Young S, Skalnik DG, Huang TH, Nephew KP (2005) Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer. Mol Cancer Ther 4(10):1505–1514PubMedGoogle Scholar
  71. 71.
    Yoo CB, Chuang JC, Byun HM, Egger G, Yang AS, Dubeau L, Long T, Laird PW, Marquez VE, Jones PA (2008) Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice. Cancer Prev Res 1(4):233–240Google Scholar
  72. 72.
    Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE, Jones PA, Selker EU (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95(5):399–409PubMedGoogle Scholar
  73. 73.
    Cheng JC, Yoo CB, Weisenberger DJ, Chuang J, Wozniak C, Liang G, Marquez VE, Greer S, Orntoft TF, Thykjaer T, Jones PA (2004) Preferential response of cancer cells to zebularine. Cancer Cell 6(2):151–158PubMedGoogle Scholar
  74. 74.
    Yoo CB, Valente R, Congiatu C, Gavazza F, Angel A, Siddiqui MA, Jones PA, McGuigan C, Marquez VE (2008) Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine. J Med Chem 51(23):7593–7601PubMedGoogle Scholar
  75. 75.
    Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, Taja-Chayeb L, Mariscal I, Chavez A, Acuna C, Salazar AM, Lizano M, Duenas-Gonzalez A (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
  76. 76.
    Chuang JC, Yoo CB, Kwan JM, Li TW, Liang G, Yang AS, Jones PA (2005) Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine. Mol Cancer Ther 4(10):1515–1520PubMedGoogle Scholar
  77. 77.
    Liu F, Liu Q, Yang D, Bollag WB, Robertson K, Wu P, Liu K (2011) Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3. Cancer Res 71(21):6807–6816PubMedGoogle Scholar
  78. 78.
    Brueckner B, Garcia Boy R, Siedlecki P, Musch T, Kliem HC, Zielenkiewicz P, Suhai S, Wiessler M, Lyko F (2005) Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 65(14):6305–6311PubMedGoogle Scholar
  79. 79.
    Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, Redkar S, Jacob ST (2009) A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res 69(10):4277–4285PubMedGoogle Scholar
  80. 80.
    Medina-Franco JL, Caulfield T (2011) Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today 16:418–425PubMedGoogle Scholar
  81. 81.
    Siedlecki P, Garcia Boy R, Musch T, Brueckner B, Suhai S, Lyko F, Zielenkiewicz P (2006) Discovery of two novel, small-molecule inhibitors of DNA methylation. J Med Chem 49(2):678–683PubMedGoogle Scholar
  82. 82.
    Medina-Franco JL, Caulfield T (2011) Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today 16(9–10):418–425PubMedGoogle Scholar
  83. 83.
    Castellano S, Kuck D, Viviano M, Yoo J, Lopez-Vallejo F, Conti P, Tamborini L, Pinto A, Medina-Franco JL, Sbardella G (2011) Synthesis and biochemical evaluation of delta(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors. J Med Chem 54(21):7663–7677PubMedGoogle Scholar
  84. 84.
    Balch C, Nephew KP (2010) The role of chromatin, microRNAs, and tumor stem cells in ovarian cancer. Cancer Biomark 8(4):203–221PubMedGoogle Scholar
  85. 85.
    Wood TE, Dalili S, Simpson CD, Sukhai MA, Hurren R, Anyiwe K, Mao X, Suarez Saiz F, Gronda M, Eberhard Y, MacLean N, Ketela T, Reed JC, Moffat J, Minden MD, Batey RA, Schimmer AD (2010) Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol Cancer Ther 9(1):246–256PubMedGoogle Scholar
  86. 86.
    Hirata H, Hinoda Y, Nakajima K, Kawamoto K, Kikuno N, Ueno K, Yamamura S, Zaman MS, Khatri G, Chen Y, Saini S, Majid S, Deng G, Ishii N, Dahiya R (2011) Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma. Int J Cancer 128(8):1793–1803PubMedGoogle Scholar
  87. 87.
    Liu T, Zhang X, So CK, Wang S, Wang P, Yan L, Myers R, Chen Z, Patterson AP, Yang CS, Chen X (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28(2):488–496PubMedGoogle Scholar
  88. 88.
    Xu J, Zhou JY, Tainsky MA, Wu GS (2007) Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2′-deoxycytidine sensitizes human breast cancer cells to adriamycin. Cancer Res 67(3):1203–1211PubMedGoogle Scholar
  89. 89.
    Chun SG, Zhou W, Yee NS (2009) Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. Cancer Biol Ther 8(14):1328–1339PubMedGoogle Scholar
  90. 90.
    Neil GL, Berger AE, Bhuyan BK, DeSante DC (1976) Combination chemotherapy of L1210 leukemia with 1-beta-D-arabinofuranosylcytosine and 5-azacytidine. Cancer Res 36(3):1114–1120PubMedGoogle Scholar
  91. 91.
    Neil GL, Moxley TE, Kuentzel SL, Manak RC, Hanka LJ (1975) Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. Cancer Chemother Pharmacol 59(3):459–465Google Scholar
  92. 92.
    Festuccia C, Gravina GL, D’Alessandro AM, Muzi P, Millimaggi D, Dolo V, Ricevuto E, Vicentini C, Bologna M (2009) Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr Relat Cancer 16(2):401–413PubMedGoogle Scholar
  93. 93.
    Anzai H, Frost P, Abbruzzese JL (1992) Synergistic cytotoxicity with 2′-deoxy-5-azacytidine and topotecan in vitro and in vivo. Cancer Res 52(8):2180–2185PubMedGoogle Scholar
  94. 94.
    Balch C, Montgomery JS, Paik HI, Kim S, Kim S, Huang TH, Nephew KP (2005) New anti-cancer strategies: epigenetic therapies and biomarkers. Front Biosci 10:1897–1931PubMedGoogle Scholar
  95. 95.
    Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R (2000) Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 60(21):6039–6044PubMedGoogle Scholar
  96. 96.
    Morita S, Iida S, Kato K, Takagi Y, Uetake H, Sugihara K (2006) The synergistic effect of 5-aza-2′-deoxycytidine and 5-fluorouracil on drug-resistant tumors. Oncology 71(5–6):437–445PubMedGoogle Scholar
  97. 97.
    Ishiguro M, Iida S, Uetake H, Morita S, Makino H, Kato K, Takagi Y, Enomoto M, Sugihara K (2007) Effect of combined therapy with low-dose 5-aza-2′-deoxycytidine and irinotecan on colon cancer cell line HCT-15. Ann Surg Oncol 14(5):1752–1762PubMedGoogle Scholar
  98. 98.
    Karpf AR, Peterson PW, Rawlins JT, Dalley BK, Yang Q, Albertsen H, Jones DA (1999) Inhibition of DNA methyltransferase stimulates the expression of signal transducer and ­activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc Natl Acad Sci USA 96(24):14007–14012PubMedGoogle Scholar
  99. 99.
    Phuong NT, Kim SK, Lim SC, Kim HS, Kim TH, Lee KY, Ahn SG, Yoon JH, Kang KW (2011) Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells. Breast Cancer Res Treat 130(1):73–83PubMedGoogle Scholar
  100. 100.
    Zuo T, Liu TM, Lan X, Weng YI, Shen R, Gu F, Huang YW, Liyanarachchi S, Deatherage DE, Hsu PY, Taslim C, Ramaswamy B, Shapiro CL, Lin HJ, Cheng AS, Jin VX, Huang TH (2011) Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer. Cancer Res 71(5):1752–1762PubMedGoogle Scholar
  101. 101.
    Stearns V, Zhou Q, Davidson NE (2007) Epigenetic regulation as a new target for breast cancer therapy. Cancer Invest 25(8):659–665PubMedGoogle Scholar
  102. 102.
    Sharma D, Saxena NK, Davidson NE, Vertino PM (2006) Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res 66(12):6370–6378PubMedGoogle Scholar
  103. 103.
    Gao L, Alumkal J (2010) Epigenetic regulation of androgen receptor signaling in prostate cancer. Epigenetics 5(2):100–104PubMedGoogle Scholar
  104. 104.
    Nelson WG, Yegnasubramanian S, Agoston AT, Bastian PJ, Lee BH, Nakayama M, De Marzo AM (2007) Abnormal DNA methylation, epigenetics, and prostate cancer. Front Biosci 12:4254–4266PubMedGoogle Scholar
  105. 105.
    Shang D, Liu Y, Liu Q, Zhang F, Feng L, Lv W, Tian Y (2009) Synergy of 5-aza-2′-deoxycytidine (DAC) and paclitaxel in both androgen-dependent and -independent prostate cancer cell lines. Cancer Lett 278(1):82–87PubMedGoogle Scholar
  106. 106.
    Zorn CS, Wojno KJ, McCabe MT, Kuefer R, Gschwend JE, Day ML (2007) 5-aza-2′-deoxycytidine delays androgen-independent disease and improves survival in the transgenic adenocarcinoma of the mouse prostate mouse model of prostate cancer. Clin Cancer Res 13(7):2136–2143PubMedGoogle Scholar
  107. 107.
    Walton TJ, Li G, Seth R, McArdle SE, Bishop MC, Rees RC (2008) DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines. Prostate 68(2):210–222PubMedGoogle Scholar
  108. 108.
    Friend C, Scher W, Holland JG, Sato T (1971) Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. Proc Natl Acad Sci USA 68(2):378–382PubMedGoogle Scholar
  109. 109.
    Marks PA, Breslow R (2007) Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25(1):84–90PubMedGoogle Scholar
  110. 110.
    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51PubMedGoogle Scholar
  111. 111.
    Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG, Gabrielli BG (2000) Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 11(6):2069–2083PubMedGoogle Scholar
  112. 112.
    Strait KA, Warnick CT, Ford CD, Dabbas B, Hammond EH, Ilstrup SJ (2005) Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2-related protein Bad. Mol Cancer Ther 4(4):603–611PubMedGoogle Scholar
  113. 113.
    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840PubMedGoogle Scholar
  114. 114.
    Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ, La Thangue NB, Brown R (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2(8):721–728PubMedGoogle Scholar
  115. 115.
    Qian X, LaRochelle WJ, Ara G, Wu F, Petersen KD, Thougaard A, Sehested M, Lichenstein HS, Jeffers M (2006) Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther 5(8):2086–2095PubMedGoogle Scholar
  116. 116.
    Uchida H, Maruyama T, Nagashima T, Asada H, Yoshimura Y (2005) Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin. Endocrinology 146(12):5365–5373PubMedGoogle Scholar
  117. 117.
    Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Miyakawa I, Koeffler HP (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10(3):1141–1149PubMedGoogle Scholar
  118. 118.
    Rahman R, Grundy R (2011) Histone deacetylase inhibition as an anticancer telomerase-targeting strategy. Int J Cancer 129(12):2765–2774PubMedGoogle Scholar
  119. 119.
    Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26(37):5541–5552PubMedGoogle Scholar
  120. 120.
    Cooper AL, Greenberg VL, Lancaster PS, van Nagell JR Jr, Zimmer SG, Modesitt SC (2007) In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. Gynecol Oncol 104:596–601PubMedGoogle Scholar
  121. 121.
    Dietrich CS III, Greenberg VL, DeSimone CP, Modesitt SC, van Nagell JR, Craven R, Zimmer SG (2010) Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel-induced apoptosis in ovarian cancer cell lines. Gynecol Oncol 116(1):126–130PubMedGoogle Scholar
  122. 122.
    Sonnemann J, Gange J, Pilz S, Stotzer C, Ohlinger R, Belau A, Lorenz G, Beck JF (2006) Comparative evaluation of the treatment efficacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients. BMC Cancer 6:183PubMedGoogle Scholar
  123. 123.
    Zuco V, Benedetti V, De Cesare M, Zunino F (2010) Sensitization of ovarian carcinoma cells to the atypical retinoid ST1926 by the histone deacetylase inhibitor, RC307: enhanced DNA damage response. Int J Cancer 126(5):1246–1255PubMedGoogle Scholar
  124. 124.
    Son DS, Wilson AJ, Parl AK, Khabele D (2010) The effects of the histone deacetylase inhibitor romidepsin (FK228) are enhanced by aspirin (ASA) in COX-1 positive ovarian cancer cells through augmentation of p21. Cancer Biol Ther 9(11):928–935PubMedGoogle Scholar
  125. 125.
    Yang YT, Balch C, Kulp SK, Mand MR, Nephew KP, Chen CS (2009) A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. Neoplasia 11(6):552–563; 553 p following 563Google Scholar
  126. 126.
    Iwahashi S, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Mori H, Hanaoka J, Saito Y (2011) Histone deacetylase inhibitor enhances the anti-tumor effect of gemcitabine: a special reference to gene-expression microarray analysis. Oncol Rep 26(5):1057–1062PubMedGoogle Scholar
  127. 127.
    Kim MS, Baek JH, Chakravarty D, Sidransky D, Carrier F (2005) Sensitization to UV-induced apoptosis by the histone deacetylase inhibitor trichostatin A (TSA). Exp Cell Res 306(1):94–102PubMedGoogle Scholar
  128. 128.
    Roh MS, Kim CW, Park BS, Kim GC, Jeong JH, Kwon HC, Suh DJ, Cho KH, Yee SB, Yoo YH (2004) Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells. Apoptosis 9(5):583–589PubMedGoogle Scholar
  129. 129.
    Srivastava RK, Kurzrock R, Shankar S (2010) MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo. Mol Cancer Ther 9(12):3254–3266PubMedGoogle Scholar
  130. 130.
    Hacker S, Dittrich A, Mohr A, Schweitzer T, Rutkowski S, Krauss J, Debatin KM, Fulda S (2009) Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene 28(35):3097–3110PubMedGoogle Scholar
  131. 131.
    Schuler S, Fritsche P, Diersch S, Arlt A, Schmid RM, Saur D, Schneider G (2010) HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells. Mol Cancer Ther 9:80Google Scholar
  132. 132.
    Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, Lauer UM, Bitzer M (2006) HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 43(3):425–434PubMedGoogle Scholar
  133. 133.
    Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN (2011) Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat 130(2):437–447PubMedGoogle Scholar
  134. 134.
    Dowdy SC, Jiang S, Zhou XC, Hou X, Jin F, Podratz KC, Jiang SW (2006) Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Mol Cancer Ther 5(11):2767–2776PubMedGoogle Scholar
  135. 135.
    Ahn MY, Chung HY, Choi WS, Lee BM, Yoon S, Kim HS (2010) Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4. Int J Oncol 36(1):125–131PubMedGoogle Scholar
  136. 136.
    Bali P, Pranpat M, Swaby R, Fiskus W, Yamaguchi H, Balasis M, Rocha K, Wang HG, Richon V, Bhalla K (2005) Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2. Clin Cancer Res 11(17):6382–6389PubMedGoogle Scholar
  137. 137.
    Morey L, Brenner C, Fazi F, Villa R, Gutierrez A, Buschbeck M, Nervi C, Minucci S, Fuks F, Di Croce L (2008) MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. Mol Cell Biol 28(19):5912–5923PubMedGoogle Scholar
  138. 138.
    Terasawa K, Sagae S, Toyota M, Tsukada K, Ogi K, Satoh A, Mita H, Imai K, Tokino T, Kudo R (2004) Epigenetic inactivation of TMS1/ASC in ovarian cancer. Clin Cancer Res 10(6):2000–2006PubMedGoogle Scholar
  139. 139.
    Chen MY, Liao WS, Lu Z, Bornmann WG, Hennessey V, Washington MN, Rosner GL, Yu Y, Ahmed AA, Bast RC Jr (2011) Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy. Cancer 117(19):4424–4438PubMedGoogle Scholar
  140. 140.
    Xiong Y, Dowdy SC, Gonzalez Bosquet J, Zhao Y, Eberhardt NL, Podratz KC, Jiang SW (2005) Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines. Gynecol Oncol 99(1):135–141PubMedGoogle Scholar
  141. 141.
    Belinsky SA, Grimes MJ, Picchi MA, Mitchell HD, Stidley CA, Tesfaigzi Y, Channell MM, Liu Y, Casero RA Jr, Baylin SB, Reed MD, Tellez CS, March TH (2011) Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res 71(2):454–462PubMedGoogle Scholar
  142. 142.
    Ecke I, Petry F, Rosenberger A, Tauber S, Monkemeyer S, Hess I, Dullin C, Kimmina S, Pirngruber J, Johnsen SA, Uhmann A, Nitzki F, Wojnowski L, Schulz-Schaeffer W, Witt O, Hahn H (2009) Antitumor effects of a combined 5-aza-2′deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res 69(3):887–895PubMedGoogle Scholar
  143. 143.
    Herranz D, Serrano M (2010) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10(12):819–823PubMedGoogle Scholar
  144. 144.
    Nebbioso A, Pereira R, Khanwalkar H, Matarese F, Garcia-Rodriguez J, Miceli M, Logie C, Kedinger V, Ferrara F, Stunnenberg HG, de Lera AR, Gronemeyer H, Altucci L (2011) Death receptor pathway activation and increase of ROS production by the triple epigenetic inhibitor, UVI5008. Mol Cancer Ther 10(12):2394–2404PubMedGoogle Scholar
  145. 145.
    Milutinovic S, D’Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 28(3):560–571PubMedGoogle Scholar
  146. 146.
    Dong E, Guidotti A, Grayson DR, Costa E (2007) Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci USA 104(11):4676–4681PubMedGoogle Scholar
  147. 147.
    Arzenani MK, Zade AE, Ming Y, Vijverberg SJ, Zhang Z, Khan Z, Sadique S, Kallenbach L, Hu L, Vukojevic V, Ekstrom TJ (2011) Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics. Mol Cell Biol 31(19):4119–4128PubMedGoogle Scholar
  148. 148.
    Ou JN, Torrisani J, Unterberger A, Provencal N, Shikimi K, Karimi M, Ekstrom TJ, Szyf M (2007) Histone deacetylase inhibitor Trichostatin A induces global and gene-specific DNA demethylation in human cancer cell lines. Biochem Pharmacol 73(9):1297–1307PubMedGoogle Scholar
  149. 149.
    Xiong Y, Dowdy SC, Podratz KC, Jin F, Attewell JR, Eberhardt NL, Jiang SW (2005) Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells. Cancer Res 65(7):2684–2689PubMedGoogle Scholar
  150. 150.
    Scott SA, Dong WF, Ichinohasama R, Hirsch C, Sheridan D, Sanche SE, Geyer CR, Decoteau JF (2006) 5-Aza-2′-deoxycytidine (decitabine) can relieve p21WAF1 repression in human acute myeloid leukemia by a mechanism involving release of histone deacetylase 1 (HDAC1) without requiring p21WAF1 promoter demethylation. Leuk Res 30(1):69–76PubMedGoogle Scholar
  151. 151.
    Egger G, Aparicio AM, Escobar SG, Jones PA (2007) Inhibition of histone deacetylation does not block resilencing of p16 after 5-aza-2′-deoxycytidine treatment. Cancer Res 67(1):346–353PubMedGoogle Scholar
  152. 152.
    Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, Grever M, Galm O, Dauses T, Karp JE, Rudek MA, Zhao M, Smith BD, Manning J, Jiemjit A, Dover G, Mays A, Zwiebel J, Murgo A, Weng LJ, Herman JG (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66(12):6361–6369PubMedGoogle Scholar
  153. 153.
    Kaminskyy VO, Surova OV, Vaculova A, Zhivotovsky B (2011) Combined inhibition of DNA methyltransferase and histone deacetylase restores caspase-8 expression and sensitizes SCLC cells to TRAIL. Carcinogenesis 32(10):1450–1458PubMedGoogle Scholar
  154. 154.
    Steele N, Finn P, Brown R, Plumb JA (2009) Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo. Br J Cancer 100(5):758–763PubMedGoogle Scholar
  155. 155.
    Matei DE, Nephew KP (2010) Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncol 116(2):195–201PubMedGoogle Scholar
  156. 156.
    Kristensen LS, Nielsen HM, Hansen LL (2009) Epigenetics and cancer treatment. Eur J Pharmacol 625(1–3):131–142PubMedGoogle Scholar
  157. 157.
    Sigalotti L, Fratta E, Coral S, Cortini E, Covre A, Nicolay HJ, Anzalone L, Pezzani L, Di Giacomo AM, Fonsatti E, Colizzi F, Altomonte M, Calabro L, Maio M (2007) Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. J Cell Physiol 212(2):330–344PubMedGoogle Scholar
  158. 158.
    Momparler RL, Rivard GE, Gyger M (1985) Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther 30(3):277–286PubMedGoogle Scholar
  159. 159.
    Wijermans PW, Krulder JW, Huijgens PC, Neve P (1997) Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 11(suppl 1):S19–S23PubMedGoogle Scholar
  160. 160.
    Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2000) Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18(5):956–962PubMedGoogle Scholar
  161. 161.
    DeSimone J, Koshy M, Dorn L, Lavelle D, Bressler L, Molokie R, Talischy N (2002) Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99(11):3905–3908PubMedGoogle Scholar
  162. 162.
    Koshy M, Dorn L, Bressler L, Molokie R, Lavelle D, Talischy N, Hoffman R, van Overveld W, DeSimone J (2000) 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 96(7):2379–2384PubMedGoogle Scholar
  163. 163.
    Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, Bayar E, Lyons J, Rosenfeld CS, Cortes J, Kantarjian HM (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103(5):1635–1640PubMedGoogle Scholar
  164. 164.
    Invest New DrugsSchwartsmann G, Schunemann H, Gorini CN, Filho AF, Garbino C, Sabini G, Muse I, DiLeone L, Mans DR (2000) 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 18(1):83–91Google Scholar
  165. 165.
    Pohlmann P, DiLeone LP, Cancella AI, Caldas AP, Dal Lago L, Campos O Jr, Monego E, Rivoire W, Schwartsmann G (2002) 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 25(5):496–501PubMedGoogle Scholar
  166. 166.
    Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol 25(29):4603–4609PubMedGoogle Scholar
  167. 167.
    Glasspool RM, Gore M, Rustin G, McNeish I, Wilson R, Pledge S, Paul J, Mackean M, Halford S, Kaye S (2009) Randomized phase II study of in combination with carboplatin compared with carboplatin alone in patients with recurrent advanced ovarian cancer. J Clin Oncol 26(15S (May 20 suppl)):Abstract 5562Google Scholar
  168. 168.
    Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF, Sood AK, Wolf JK, Gershenson DM, Markman M, Hennessy BT, Kurzrock R, Bast RC Jr (2011) 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 117(8):1661–1669PubMedGoogle Scholar
  169. 169.
    Fang F, Balch C, Schilder J, Breen T, Zhang S, Shen C, Li L, Kulesavage C, Snyder AJ, Nephew KP, Matei DE (2010) A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer 116(17):4043–4053PubMedGoogle Scholar
  170. 170.
    Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T, Nephew KP (2012). Epigenetic resensitization to platinum in ovarian cancer. Cancer Res 72(9):2197–2205Google Scholar
  171. 171.
    Bauman J, Verschraegen C, Belinsky S, Muller C, Rutledge T, Fekrazad M, Ravindranathan M, Lee SJ, Jones D (2012) A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies. Cancer Chemother Pharmacol 69(2):547–554PubMedGoogle Scholar
  172. 172.
    George RE, Lahti JM, Adamson PC, Zhu K, Finkelstein D, Ingle AM, Reid JM, Krailo M, Neuberg D, Blaney SM, Diller L (2010) 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 55(4):629–638PubMedGoogle Scholar
  173. 173.
    Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, Abboud CN, Westervelt P, DiPersio JF, Hassan A, Cashen AF, Vij R (2011) Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. Am J Hematol 86(9):796–800PubMedGoogle Scholar
  174. 174.
    Stewart DJ, Issa JP, Kurzrock R, Nunez MI, Jelinek J, Hong D, Oki Y, Guo Z, Gupta S, Wistuba II (2009) Decitabine effect on tumor global DNA methylation and other parameters in a phase I trial in refractory solid tumors and lymphomas. Clin Cancer Res 15(11): 3881–3888PubMedGoogle Scholar
  175. 175.
    Modesitt SC, Sill M, Hoffman JS, Bender DP (2008) A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 109(2):182–186PubMedGoogle Scholar
  176. 176.
    Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P, Wang L, Mason J, Pham PA, Tsao MS, Pan J, Zwiebel J, Oza AM (2010) 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 46(9):1573–1579PubMedGoogle Scholar
  177. 177.
    Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S, Riggs CE Jr, Higano C, Stadler WM, McCulloch W, Dearnaley D, Parker C, de Bono JS (2010) Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann Oncol 21(1):109–113PubMedGoogle Scholar
  178. 178.
    Hainsworth JD, Infante JR, Spigel DR, Arrowsmith ER, Boccia RV, Burris HA (2011) A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest 29(7):451–455PubMedGoogle Scholar
  179. 179.
    Takai N, Narahara H (2010) Histone deacetylase inhibitor therapy in epithelial ovarian cancer. J Oncol 2010:458431PubMedGoogle Scholar
  180. 180.
    Thurn KT, Thomas S, Moore A, Munster PN (2011) Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol 7(2):263–283PubMedGoogle Scholar
  181. 181.
    Rodon J, Iniesta MD, Papadopoulos K (2009) Development of PARP inhibitors in oncology. Expert Opin Investig Drugs 18(1):31–43PubMedGoogle Scholar
  182. 182.
    Teicher BA (2010) Combinations of PARP, hedgehog and HDAC inhibitors with standard drugs. Curr Opin Pharmacol 10(4):397–404PubMedGoogle Scholar
  183. 183.
    Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE (2011) A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer 104(12):1828–1835PubMedGoogle Scholar
  184. 184.
    Drappatz J, Lee EQ, Hammond S, Grimm SA, Norden AD, Beroukhim R, Gerard M, Schiff D, Chi AS, Batchelor TT, Doherty LM, Ciampa AS, Lafrankie DC, Ruland S, Snodgrass SM, Raizer JJ, Wen PY (2012) Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol 107(1):133–138PubMedGoogle Scholar
  185. 185.
    Candelaria M, Herrera A, Labardini J, Gonzalez-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Perez-Cardenas E, de la Cruz-Hernandez E, Arias-Bofill D, Vidal S, Cervera E, Duenas-Gonzalez A (2011) Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 90(4):379–387PubMedGoogle Scholar
  186. 186.
    Braiteh F, Soriano AO, Garcia-Manero G, Hong D, Johnson MM, Silva Lde P, Yang H, Alexander S, Wolff J, Kurzrock R (2008) Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res 14(19):6296–6301PubMedGoogle Scholar
  187. 187.
    Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner LA, McGill S, Wang L, Zhang WJ, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17(6):1582–1590PubMedGoogle Scholar
  188. 188.
    Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, Lee BH, Tsai S, Delgado IE, Rudek MA, Belinsky SA, Herman JG, Baylin SB, Brock MV, Rudin CM (2011) Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 1:598–607PubMedGoogle Scholar
  189. 189.
    Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, Gonzalez-Fierro A, Chavez-Blanco A, de la Cruz-Hernandez E, Camargo MF, Trejo-Becerril C, Perez-Cardenas E, Perez-Plasencia C, Taja-Chayeb L, Wegman-Ostrosky T, Revilla-Vazquez A, Duenas-Gonzalez A (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):1529–1538PubMedGoogle Scholar
  190. 190.
    Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’Brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108(10):3271–3279PubMedGoogle Scholar
  191. 191.
    Gollob JA, Sciambi CJ, Peterson BL, Richmond T, Thoreson M, Moran K, Dressman HK, Jelinek J, Issa JP (2006) Phase I trial of sequential low-dose 5-aza-2′-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma. Clin Cancer Res 12(15):4619–4627PubMedGoogle Scholar
  192. 192.
    Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5(8):615–625PubMedGoogle Scholar
  193. 193.
    Karpf AR (2006) A potential role for epigenetic modulatory drugs in the enhancement of cancer/germ-line antigen vaccine efficacy. Epigenetics 1(3):116–120PubMedGoogle Scholar
  194. 194.
    Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q (2007) Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21(9):1050–1063PubMedGoogle Scholar
  195. 195.
    Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y (2011) Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J Am Chem Soc 133(42):16746–16749PubMedGoogle Scholar
  196. 196.
    Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng JC, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20(1):53–65PubMedGoogle Scholar
  197. 197.
    Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, Marquez VE, Bates SE, Jin Q, Khan J, Ge K, Thiele CJ (2012) EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3 and NGFR. Cancer Res 72(1):315–324PubMedGoogle Scholar
  198. 198.
    Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, Koh TL, Yu Q, Chng WJ (2011) The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 118(10):2830–2839PubMedGoogle Scholar
  199. 199.
    Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, Danesi R, Farrar WL (2011) Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer 10:40PubMedGoogle Scholar
  200. 200.
    Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN (2009) Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114(13):2733–2743PubMedGoogle Scholar
  201. 201.
    Hayden A, Johnson PW, Packham G, Crabb SJ (2011) S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat 127(1):109–119PubMedGoogle Scholar
  202. 202.
    Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, Marquez VE, Clement V, Stamenkovic I (2009) EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 69(24):9211–9218PubMedGoogle Scholar
  203. 203.
    Quinn AM, Allali-Hassani A, Vedadi M, Simeonov A (2010) A chemiluminescence-based method for identification of histone lysine methyltransferase inhibitors. Mol Biosyst 6(5):782–788PubMedGoogle Scholar
  204. 204.
    King ON, Li XS, Sakurai M, Kawamura A, Rose NR, Ng SS, Quinn AM, Rai G, Mott BT, Beswick P, Klose RJ, Oppermann U, Jadhav A, Heightman TD, Maloney DJ, Schofield CJ, Simeonov A (2010) Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS One 5(11):e15535PubMedGoogle Scholar
  205. 205.
    Tang W, Luo T, Greenberg EF, Bradner JE, Schreiber SL (2011) Discovery of histone deacetylase 8 selective inhibitors. Bioorg Med Chem Lett 21(9):2601–2605PubMedGoogle Scholar
  206. 206.
    Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J (2011) A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 7(8):566–574PubMedGoogle Scholar
  207. 207.
    Cole PA (2008) Chemical probes for histone-modifying enzymes. Nat Chem Biol 4(10): 590–597PubMedGoogle Scholar
  208. 208.
    Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137(6):1005–1017PubMedGoogle Scholar
  209. 209.
    Ibrahim AF, Weirauch U, Thomas M, Grunweller A, Hartmann RK, Aigner A (2011) MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res 71(15):5214–5224PubMedGoogle Scholar
  210. 210.
    Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, Ponzetto C (2009) The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 119(8):2366–2378PubMedGoogle Scholar
  211. 211.
    Avramis VI, Mecum RA, Nyce J, Steele DA, Holcenberg JS (1989) Pharmacodynamic and DNA methylation studies of high-dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in pediatric patients with refractory acute lymphocytic leukemia. Cancer Chemother Pharmacol 24(4):203–210PubMedGoogle Scholar
  212. 212.
    Belinsky SA, Klinge DM, Stidley CA, Issa JP, Herman JG, March TH, Baylin SB (2003) Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res 63(21):7089–7093PubMedGoogle Scholar
  213. 213.
    Goldberg J, Gryn J, Raza A, Bennett J, Browman G, Bryant J, Grunwald H, Larson R, Vogler R, Preisler H (1993) Mitoxantrone and 5-azacytidine for refractory/relapsed ANLL or CML in blast crisis: a leukemia intergroup study. Am J Hematol 43(4):286–290PubMedGoogle Scholar
  214. 214.
    Hakami N, Look AT, Steuber PC, Krischer J, Castleberry R, Harris R, Ravindranath Y, Vietti TJ (1987) Combined etoposide and 5-azacitidine in children and adolescents with refractory or relapsed acute nonlymphocytic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 5(7):1022–1025PubMedGoogle Scholar
  215. 215.
    Huang Y, Nayak S, Jankowitz R, Davidson NE, Oesterreich S (2011) Epigenetics in breast cancer: what’s new? Breast Cancer Res 13(6):225PubMedGoogle Scholar
  216. 216.
    Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300PubMedGoogle Scholar
  217. 217.
    Leshin M (1985) 5-Azacytidine and sodium butyrate induce expression of aromatase in fibroblasts from chickens carrying the henny feathering trait but not from wild-type chickens. Proc Natl Acad Sci USA 82(9):3005–3009PubMedGoogle Scholar
  218. 218.
    Liu WH, Yung BY (1998) Mortalization of human promyelocytic leukemia HL-60 cells to be more susceptible to sodium butyrate-induced apoptosis and inhibition of telomerase activity by down-regulation of nucleophosmin/B23. Oncogene 17(23):3055–3064PubMedGoogle Scholar
  219. 219.
    Momparler RL, Bouffard DY, Momparler LF, Dionne J, Belanger K, Ayoub J (1997) Pilot phase I-II study on 5-aza-2′-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anticancer Drugs 8(4):358–368PubMedGoogle Scholar
  220. 220.
    Pollyea DA, Kohrt HE, Gallegos L, Figueroa ME, Abdel-Wahab O, Zhang B, Bhattacharya S, Zehnder J, Liedtke M, Gotlib JR, Coutre S, Berube C, Melnick A, Levine R, Mitchell BS, Medeiros BC (2012) Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 26(5):893–901PubMedGoogle Scholar
  221. 221.
    Schwartsmann G, Fernandes MS, Schaan MD, Moschen M, Gerhardt LM, Di Leone L, Loitzembauer B, Kalakun L (1997) Decitabine (5-Aza-2′-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11(suppl 1):S28–S31PubMedGoogle Scholar
  222. 222.
    Willemze R, Archimbaud E, Muus P (1993) Preliminary results with 5-aza-2′-deoxycytidine (DAC)-containing chemotherapy in patients with relapsed or refractory acute leukemia. The EORTC Leukemia Cooperative Group. Leukemia 7(suppl 1):49–50PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Medical SciencesIndiana University School of Medicine, Indiana University School of MedicineBloomingtonUSA
  2. 2.Melvin and Bren Simon Cancer CenterIndiana UniversityIndianapolisUSA
  3. 3.Medical SciencesIndiana University School of MedicineBloomingtonUSA
  4. 4.Department of Cellular and Integrative PhysiologyIndiana University School of MedicineIndianapolisUSA
  5. 5.Department of Obstetrics and Gynecology, Department of MedicineIndiana University School of MedicineIndianapolisUSA
  6. 6.Medical Sciences Program, Department of Cellular and Integrative PhysiologyIndiana University School of MedicineBloomingtonUSA

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