Epigenetic targeting therapies to overcome chemotherapy resistance

Advances in Experimental Medicine and Biology

Volumn 754, Issue , 2013, Pages 285-311

  Balch, Curt ^a,b   Nephew, Kenneth P ^a,b,c  

^a Indiana University School of Medicine   (United States)

^b INDIANA UNIVERSITY   (United States)

^c INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; ARSENIC TRIOXIDE; ASCORBIC ACID; AZACITIDINE; BELINOSTAT; BEVACIZUMAB; BUTYRIC ACID; CANCER VACCINE; CARBOPLATIN; CISPLATIN; CYCLOPHOSPHAMIDE; CYTARABINE; DAUNORUBICIN; DNA METHYLTRANSFERASE INHIBITOR; DOXORUBICIN; ERLOTINIB; ETOPOSIDE; HISTONE DEACETYLASE INHIBITOR; HYDRALAZINE; LENALIDOMIDE; MITOXANTRONE; PACLITAXEL; PANOBINOSTAT; PLATINUM COMPLEX; RETINOIC ACID; ROMIDEPSIN; TAMOXIFEN; UNINDEXED DRUG; VALPROIC ACID; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ARTICLE; BLOOD TOXICITY; BONE MARROW SUPPRESSION; BRAIN DISEASE; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CANCER STEM CELL; CHILDHOOD LEUKEMIA; DIAGNOSTIC TEST; DISEASE MARKER; DRUG FATALITY; DRUG MEGADOSE; DRUG POTENTIATION; DRUG RESPONSE; DRUG TARGETING; DRUG TOXICITY; EPIGENETICS; GENE EXPRESSION; HUMAN; KIDNEY CANCER; LOW DRUG DOSE; LUNG CANCER; LUNG METASTASIS; LUNG NON SMALL CELL CANCER; MALIGNANT TRANSFORMATION; METASTASIS; MYELODYSPLASTIC SYNDROME; NEUROBLASTOMA; NONHUMAN; OVARY CANCER; PERITONEUM CANCER; PRIORITY JOURNAL; PROSTATE CANCER; SOLID TUMOR; TRIPLE NEGATIVE BREAST CANCER; TUMOR SUPPRESSOR GENE; UNSPECIFIED SIDE EFFECT; UTERINE CERVIX CARCINOMA;

EID: 84869064386     PISSN: 00652598     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-4419-9967-2_14     Document Type: Article

References (222)

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):313-325
2. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277-300
3. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275-292 (Pubitemid 40227997)
4. Raguz S, Yague E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99(3):387-391
5. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441-1454
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):1552-1572 (Pubitemid 39491180)
7. Barton CA, Clark SJ, Hacker NF, O'Brien PM (2008) Epigenetic markers of ovarian cancer. Adv Exp Med Biol 622:35-51
8. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683-692 (Pubitemid 46273572)
9. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148-1159
10. Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17(3):330-339
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):10117-10122 (Pubitemid 350070782)
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):299-308 (Pubitemid 44036559)
13. Daley GQ (2008) Common themes of dedifferentiation in somatic cell reprogramming and cancer. Cold Spring Harb Symp Quant Biol 73:171-174
14. Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7(6):505-512 (Pubitemid 40799244)
15. Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267-284 (Pubitemid 46706514)
16. Jordan CT (2009) Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4(3):203-205
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):237-245
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):10635-10637 (Pubitemid 350145885)
19. Ma WW, Adjei AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59(2):111-137
20. Vincent A, Van Seuningen I (2009) Epigenetics, stem cells and epithelial cell fate. Differentiation 78(2-3):99-107
21. Scaf fi di P, Misteli T (2010) Cancer epigenetics: from disruption of differentiation programs to the emergence of cancer stem cells. Cold Spring Harb Symp Quant Biol 75:251-258
22. Lotem J, Sachs L (2006) Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene 25(59):7663-7672 (Pubitemid 44967961)
23. Djuric U, Ellis J (2010) Epigenetics of induced pluripotency, the seven-headed dragon. Stem Cell Res Ther 1(1):3
24. Hochedlinger K, Plath K (2009) Epigenetic reprogramming and induced pluripotency. Development 136(4):509-523
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):387-398
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):246-255 (Pubitemid 46480969)
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):309-505
28. Ney PA, D'Andrea AD (2000) Friend erythroleukemia revisited. Blood 96(12):3675-3680
29. Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20(1):85-93 (Pubitemid 10117303)
30. Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27(32):5459-5468
31. Yang X, Lay F, Han H, Jones PA (2010) Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci 31(11):536-546
32. Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res 13(6):1634-1637
33. Ewald B, Sampath D, Plunkett W (2008) Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27(50):6522-6537
34. Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5(1):37-50
35. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H (2008) Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 112(11):2341-2351
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 29:2060-2076
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):819-830
38. Takai N, Kawamata N, Walsh CS, Gery S, Desmond JC, Whittaker S, Said JW, Popoviciu LM, Jones PA, Miyakawa I, Koef fl er HP (2005) Discovery of epigenetically masked tumor suppressor genes in endometrial cancer. Mol Cancer Res 3(5):261-269 (Pubitemid 40656813)
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):201-207 (Pubitemid 36593413)
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):6456-6461 (Pubitemid 35364106)
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):5582-5591 (Pubitemid 43927108)
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):81-85 (Pubitemid 12205566)
43. Taylor SM, Jones PA (1982) Mechanism of action of eukaryotic DNA methyltransferase. Use of 5-azacytosine-containing DNA. J Mol Biol 162(3):679-692 (Pubitemid 13113000)
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):20-27
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):405-411
46. Walker C, Shay JW (1984) 5-Azacytidine induced myogenesis in a differentiation defective cell line. Differentiation 25(3):259-263 (Pubitemid 14158691)
47. Liu L, Harrington M, Jones PA (1986) Characterization of myogenic cell lines derived by 5-azacytidine treatment. Dev Biol 117(2):331-336 (Pubitemid 17170353)
48. Hustad CM, Jones PA (1991) Effect of myogenic determination on tumorigenicity of chemically transformed 10T1/2 cells. Mol Carcinog 4(2):153-161
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):525-536 (Pubitemid 40189549)
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):922-931 (Pubitemid 29119540)
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):581-588 (Pubitemid 38256407)
52. Balch C, Montgomery JS, Paik HI, Kim S, Huang TH, Nephew KP (2005) New anti-cancer strategies: epigenetic therapies and biomarkers. Front Biosci 10:1897-1931 (Pubitemid 40532955)
53. Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2′ -deoxycytidine (decitabine). Semin Oncol 32(5):443-451 (Pubitemid 41396420)
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):3493-3496 (Pubitemid 13026595)
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):1361-1366 (Pubitemid 16199177)
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):977-982 (Pubitemid 23330150)
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):3352-3356 (Pubitemid 29334490)
58. Schnekenburger M, Grandjenette C, Ghel fi 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):364-378
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) Identi fi cation of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9(17):6410-6418 (Pubitemid 38031827)
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):18-29
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):823-831
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):543-551
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):766-776
64. Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y (2010) Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. Carcinogenesis 31(5):777-784
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):4116-4121 (Pubitemid 44024874)
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):1443-1450
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):6400-6408 (Pubitemid 47037524)
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 esteri fi cation increases therapeutic drug ef fi cacy. Mol Cancer Ther 9(5):1256-1264
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):6110-6115 (Pubitemid 37255146)
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):1505-1514 (Pubitemid 41556432)
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):233-240
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):399-409 (Pubitemid 36395260)
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):151-158 (Pubitemid 39485687)
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):7593-7601
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):1596-1603 (Pubitemid 36554581)
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):1515-1520 (Pubitemid 41556433)
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):6807-6816
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):6305-6311 (Pubitemid 40994416)
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):4277-4285
80. Medina-Franco JL, Caul fi eld T (2011) Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today 16:418-425
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):678-683 (Pubitemid 43157497)
82. Medina-Franco JL, Caul fi eld T (2011) Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today 16(9-10):418-425
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):7663-7677
84. Balch C, Nephew KP (2010) The role of chromatin, microRNAs, and tumor stem cells in ovarian cancer. Cancer Biomark 8(4):203-221
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):246-256
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):1793-1803
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):488-496 (Pubitemid 46321867)
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):1203-1211
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):1328-1339
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):1114-1120
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):459-465
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):401-413
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):2180-2185
94. Balch C, Montgomery JS, Paik HI, Kim S, Kim S, Huang TH, Nephew KP (2005) New anticancer strategies: epigenetic therapies and biomarkers. Front Biosci 10:1897-1931 (Pubitemid 40532955)
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):6039-6044
96. Morita S, Iida S, Kato K, Takagi Y, Uetake H, Sugihara K (2006) The synergistic effect of 5-aza-2′ -deoxycytidine and 5- fl uorouracil on drug-resistant tumors. Oncology 71(5-6):437-445 (Pubitemid 47573709)
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):1752-1762 (Pubitemid 46790993)
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):14007-14012
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):73-83
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):1752-1762
101. Stearns V, Zhou Q, Davidson NE (2007) Epigenetic regulation as a new target for breast cancer therapy. Cancer Invest 25(8):659-665 (Pubitemid 350223167)
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):6370-6378
103. Gao L, Alumkal J (2010) Epigenetic regulation of androgen receptor signaling in prostate cancer. Epigenetics 5(2):100-104
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 12:4254-4266
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):82-87
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):2136-2143 (Pubitemid 46649883)
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):210-222 (Pubitemid 351186233)
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):378-382
109. Marks PA, Breslow R (2007) Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25(1):84-90 (Pubitemid 46087907)
110. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38-51 (Pubitemid 43054973)
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):2069-2083 (Pubitemid 30408065)
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):603-611 (Pubitemid 40601842)
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):834-840
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):721-728
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):2086-2095 (Pubitemid 44336581)
116. Uchida H, Maruyama T, Nagashima T, Asada H, Yoshimura Y (2005) Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through upregulation of glycodelin. Endocrinology 146(12):5365-5373 (Pubitemid 41653050)
117. Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Miyakawa I, Koef fl er HP (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10(3):1141-1149 (Pubitemid 38198916)
118. Rahman R, Grundy R (2011) Histone deacetylase inhibition as an anticancer telomerasetargeting strategy. Int J Cancer 129(12):2765-2774
119. Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26(37):5541-5552 (Pubitemid 47255934)
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 104:596-601 (Pubitemid 46240243)
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):126-130
122. Sonnemann J, Gange J, Pilz S, Stotzer C, Ohlinger R, Belau A, Lorenz G, Beck JF (2006) Comparative evaluation of the treatment ef fi cacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients. BMC Cancer 6:183
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):1246-1255
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):928-935
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 563
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):1057-1062
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):94-102 (Pubitemid 40692775)
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):583-589 (Pubitemid 39158634)
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):3254-3266
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):3097-3110
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 9:80
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):425-434
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):437-447
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):2767-2776 (Pubitemid 44849003)
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):125-131
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 ampli fi cation of her-2. Clin Cancer Res 11(17):6382-6389 (Pubitemid 41262970)
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):5912-5923
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):2000-2006 (Pubitemid 38375559)
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):4424-4438
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):135-141 (Pubitemid 41354594)
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):454-462
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):887-895
143. Herranz D, Serrano M (2010) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10(12):819-823
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):2394-2404
145. Milutinovic S, D'Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of speci fi c genes. Carcinogenesis 28(3):560-571 (Pubitemid 46523352)
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):4676-4681 (Pubitemid 47186284)
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):4119-4128
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-speci fi c DNA demethylation in human cancer cell lines. Biochem Pharmacol 73(9):1297-1307 (Pubitemid 46452588)
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):2684-2689 (Pubitemid 40490068)
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):69-76 (Pubitemid 41654707)
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):346-353 (Pubitemid 46142794)
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):6361-6369
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):1450-1458
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):758-763
155. Matei DE, Nephew KP (2010) Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncol 116(2):195-201
156. Kristensen LS, Nielsen HM, Hansen LL (2009) Epigenetics and cancer treatment. Eur J Pharmacol 625(1-3):131-142
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):330-344 (Pubitemid 47025622)
158. Momparler RL, Rivard GE, Gyger M (1985) Clinical trial on 5-aza-2′ -deoxycytidine in patients with acute leukemia. Pharmacol Ther 30(3):277-286 (Pubitemid 17207209)
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-S23 (Pubitemid 27197354)
160. Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2000) Lowdose 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):956-962 (Pubitemid 30123770)
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):3905-3908 (Pubitemid 35332025)
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):2379-2384
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):1635-1640 (Pubitemid 38268953)
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):83-91 (Pubitemid 30175899)
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):496-501 (Pubitemid 35154957)
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):4603-4609 (Pubitemid 350035319)
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 5562
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):1661-1669
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):4043-4053
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): 2197-2205
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):547-554
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):629-638
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):796-800
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): 3881-3888
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):182-186
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):1573-1579
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):109-113
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):451-455
179. Takai N, Narahara H (2010) Histone deacetylase inhibitor therapy in epithelial ovarian cancer. J Oncol 2010:458431
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):263-283
181. Rodon J, Iniesta MD, Papadopoulos K (2009) Development of PARP inhibitors in oncology. Expert Opin Investig Drugs 18(1):31-43
182. Teicher BA (2010) Combinations of PARP, hedgehog and HDAC inhibitors with standard drugs. Curr Opin Pharmacol 10(4):397-404
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 therapyresistant breast cancer. Br J Cancer 104(12):1828-1835
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):133-138
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-Bo fi ll 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):379-387
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):6296-6301
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):1582-1590
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 ef fi cacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 1:598-607
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):1529-1538 (Pubitemid 47365487)
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):3271-3279
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):4619-4627
192. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5(8):615-625 (Pubitemid 41081387)
193. Karpf AR (2006) A potential role for epigenetic modulatory drugs in the enhancement of cancer/germ-line antigen vaccine ef fi cacy. Epigenetics 1(3):116-120
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):1050-1063 (Pubitemid 46686474)
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):16746-16749
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):53-65
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):315-324
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):2830-2839
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 10:40
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):2733-2743
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):109-119
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):9211-9218
203. Quinn AM, Allali-Hassani A, Vedadi M, Simeonov A (2010) A chemiluminescence-based method for identi fi cation of histone lysine methyltransferase inhibitors. Mol Biosyst 6(5):782-788
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, Scho fi eld CJ, Simeonov A (2010) Quantitative high-throughput screening identi fi es 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS One 5(11):e15535
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):2601-2605
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):566-574
207. Cole PA (2008) Chemical probes for histone-modifying enzymes. Nat Chem Biol 4(10): 590-597
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):1005-1017
209. Ibrahim AF, Weirauch U, Thomas M, Grunweller A, Hartmann RK, Aigner A (2011) MicroRNA replacement therapy for miR-145 and miR-33a is ef fi cacious in a model of colon carcinoma. Cancer Res 71(15):5214-5224
210. Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, Ponzetto C (2009) The muscle-speci fi c microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 119(8):2366-2378
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):203-210 (Pubitemid 19176799)
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):7089-7093 (Pubitemid 37413444)
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):286-290 (Pubitemid 23205209)
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):1022-1025 (Pubitemid 18056007)
215. Huang Y, Nayak S, Jankowitz R, Davidson NE, Oesterreich S (2011) Epigenetics in breast cancer: what's new? Breast Cancer Res 13(6):225
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):7291-7300 (Pubitemid 37413470)
217. Leshin M (1985) 5-Azacytidine and sodium butyrate induce expression of aromatase in fi broblasts from chickens carrying the henny feathering trait but not from wild-type chickens. Proc Natl Acad Sci USA 82(9):3005-3009 (Pubitemid 15097781)
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):3055-3064 (Pubitemid 29012209)
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):358-368 (Pubitemid 27204954)
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, ef fi cacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 26(5):893-901
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 fi rst line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11(suppl 1):S28-S31
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):49-50 (Pubitemid 23184800)