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Review Article Volume 4 Issue 10

Strategic Therapies with Epigenetic Drugs: A Review

Daniela Maria Capuano1,3, Rosanna Cipolla3 and Roberto Verna1-3*

1World Association of Societies of Pathology and Laboratory Medicine, IL, USA
2UniCamillus University, Rome, Italy
3Center for Sports Medicine and Management, Sapienza University of Rome, Italy

*Corresponding Author: Roberto Verna, World Association of Societies of Pathology and Laboratory Medicine, IL, USA and UniCamillus University, Center for Sports Medicine and Management, Sapienza University of Rome, Italy.

Received: July 30, 2020; Published: September 28, 2020

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Abstract

  With recent advances in DNA sequencing (high-throughput analysis), researchers have been able to examine epigenetic changes across the whole genome, and recent studies have shown that epigenetics play a central role in many types of diseases. Epigenetic variations have been found in various pathologies and their involvement in the cancerous transformation has been demonstrated. Given that epigenetic dysregulation is potentially reversible and given that many diseases have an epigenetic etiology, the researchers hypothesized that inhibition epigenetic changes may have therapeutic potential. This is what has encouraged the development of new pharmacological opportunities that can be defined with the term "epigenetic therapy". A number of epigenetic drugs have already been approved or are currently undergoing clinical trials. This paper is a review of the literature to illustrate the therapeutic potential of these drugs and evaluate their clinical application.

Keywords: DNA Sequencing; Epigenetic Therapy; Epigenetic Dysregulation

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References

  1. Waddington CH. "The epigenotype“. Endeavour 1 (1942): 18-20.
  2. Holliday R. “Mechanisms for the control of gene activity during development”. Biological Reviews of the Cambridge Philosophical Society 65 (1990): 431-471.
  3. Russo VEA., et al. “Epigenetic mechanisms of gene regulation”. Plainview, NY: Cold Spring Harbor Laboratory Press (1996).
  4. Jenuwein T and Allis CD. “Translating the histone code”. Science5532 (2001): 1074-1080.
  5. Jaenisch R and Bird A. “Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals”. Nature Genetics 33 (2003): 245-254.
  6. Feinberg AP and Vogelstein B. “Hypomethylation distinguishes genes of some human cancers from their normal counterparts”. Nature 301 (1983): 89-
  7. Rodenhiser D and Mann M. “Epigenetics and human disease: translating basic biology into clinical applications”. CMAJ : Canadian Medical Association Journal3 (2006): 341-348.
  8. Egger G., et al. “Epigenetics in human disease and prospects for epigenetic therapy”. Nature 429 (2004): 457-463.
  9. Morgan, HD., et al. “Epigenetic reprogramming in mammals”. Human Molecular Genetics 14 (2005): R47-58.
  10. Robertson KD. “DNA methylation and chromatin — unraveling the tangled web”. Oncogene 21 (2002): 5361-5379.
  11. Bird A. “DNA methylation patterns and epigenetic memory”. Genes and Development 16 (2002): 6-21.
  12. Miranda TB and Jones PA. “DNA methylation: the nuts and bolts of repression”. Journal of Cellular Physiology 213 (2007): 384-390.
  13. Cheung P and Lau P. “Epigenetic Regulation by Histone Methylation and Histone Variants”. Molecular Endocrinology 3 (2005): 563-573.
  14. Borrelli E., et al. “Decoding the Epigenetic Language of Neuronal Plasticity”. Neuron 6 (2008): 961-974.
  15. Peterson CL and Laniel MA. “Histones and histone modifications”. Current 14 (2004): R546-551.
  16. Berger SL. “The complex language of chromatin regulation during transcription”. Nature 447 (2007): 407-412.
  17. Elgin SC and Grewal SI. “Heterochromatin: Silence is golden”. Current Biology 13 (2003): R895-898.
  18. Ehrenhofer-Murray AE. “Chromatin dynamics at DNA replication, transcription and repair”. European Journal of Biochemistry 271 (2004): 2335-2349.
  19. Verona RI., et al. “Genomic imprinting: intricacies of epi- genetic regulation in clusters”. Annual Review of Cell and Developmental Biology 19 (2003): 237-259.
  20. Avner P and Heard E. “X-chromosome inactivation: counting, choice and initiation”. Nature Reviews Genetics 2 (2001): 59-67.
  21. Nicholls RD and Knepper JL. “Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes”. Annual Review of Genomics and Human Genetics 2 (2001).
  22. Weksberg R., et al. “Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development”. Human Molecular Genetics 12 (2003): R61-68.
  23. Kamnasaran D and Cox DW. “Current status of human chromosome 14”. Journal of Medical Genetics 39 (2002): 81-90.
  24. Peter A Jones., et al. “The fundamental role of epigenetic events in cancer”. Nature Reviews Genetics 3 (2002): 415-428.
  25. Esteller M., et al. “A gene hypermethylation profile of human cancer”. Cancer Research8 (2001): 3225-3229.
  26. Weber M., et al. “Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells”. Nature Genetics8 (2005): 853-862.
  27. Kane MF., et al. “Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines”. Cancer Research 57 (1997): 808-811.
  28. Cottrell SE. “Molecular diagnostic applications of DNA methylation technology”. Clinical Biochemistry 37 (2004): 595-604.
  29. Richardson B. “Impact of aging on DNA methylation”. Ageing Research Reviews 2 (2003): 245-261.
  30. Fitzpatrick DR and Wilson CB. “Methylation and demethylation in the regulation of genes, cells, and responses in the immune system”. Clinical Immunology 109 (2003): 37-45.
  31. Bergman Y and Cedar H. “A stepwise epigenetic process controls immunoglobulin allelic exclusion”. Nature Review on Immunology 4 (2004): 753-761.
  32. Oelke K and Richardson B. “Decreased T cell ERK pathway signaling may contribute to the development of lupus through effects on DNA methylation and gene expression”. International Reviews of Immunology 23 (2004): 315-331.
  33. Abdolmaleky HM., et al. “Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation”. American Journal of Medical Genetics 127 (2004): 51-59.
  34. Chen Y., et al. “On the epigenetic regulation of the human reelin promoter”. Nucleic Acids Research 30 (2002): 2930-2939.
  35. Mulder C., et al. “The transmethylation cycle in the brain of Alzheimer patients”. Neuroscience Letter 386 (2005): 69-71.
  36. Kriaucionis S and Bird A. “DNA methylation and Rett syndrome”. Human Molecular Genetics 12 (2003): R221-227.
  37. Laird PW. "Cancer epigenetics”. Human Molecular Genetics 14 (2005): R65-76.
  38. Tambaro FP., et al. “Histone deacetylase inhibitors: clinical implications for hematological malignancies. Clinical Epigenetics1-2 (2010): 25-44.
  39. Rasmussen TA., et al. “Eliminating the latent HIV reservoir by reactivation strategies”. Human Vaccines and Immunotherapeutics 4 (2013): 790-799.
  40. A O'Connor., et al. “Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study”. Journal of Clinical Oncology 33 (2015): 2492-2499.
  41. Carafa V., et al. “Sirtuins and disease: the road ahead”. Frontiers in Pharmacology 3 (2012): 4.
  42. Ren M., et al. “Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction”. Journal of Neurochemistry 89 (2004): 1358-1367.
  43. Esteller M. “DNA methylation and cancer therapy: new developments and expectations”. Current Opinion in Oncology 17 (2005): 55-60.
  44. Kaminskas E., et al. “FDA drug approval summary: azacitidine (5-azacytidine, VidazaTM) for injectable suspension”. Oncologist 10 (2005): 176-182.
  45. Santi DV., et al. “Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine”. Proceedings of the National Academy of Sciences of the United States of America 81 (1984): 6993-6997.
  46. Nakamura K., et al. “DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis”. PLoS One1 (2013): e54036.
  47. Brueckner B., et al. “Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases”. Cancer Research 65 (2005): 6305-6311.
  48. Zambrano P., et al. “A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes”. BMC Cancer 5 (2005): 44.
  49. Candelaria M., et al. “A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors”. Annuals of Oncology 18 (2007): 1529-1538.
  50. Fang MZ., et al. “Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines”. Cancer Research 63 (2003): 7563-7570.
  51. Davis AJ., et al. “Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks”. Investigation on New Drugs 21 (2003): 85-97.
  52. Winquist E., et al. “Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study”. Investigation on New Drugs 24 (2006): 159-167.
  53. Amato RJ., et al. “MG98, a Second-Generation DNMT1 Inhibitor, in the Treatment of Advanced Renal Cell Carcinoma”. Cancer Investigation5 (2012).
  54. Amatori S., et al. “DNA Demethylating Antineoplastic Strategies: A Comparative Point of View”. Genes and Cancer 3 (2010): 197-209.
  55. Sterner DE nad Berger SL. “Acetylation of Histones and Transcription-Related Factors”. Microbiology and Molecular Biology Reviews2 (2000): 435-459.
  56. Balasubramanyam K., et al. “Polyisoprenylated benzophenone, Garcinol, a natural histone acetyltransferase inhibitor, Represses chromatin transcription and alters global gene expression”. Journal of Biological Chemistry (2004): 279.
  57. Hemshekhar M., et al. “Emerging roles of anacardic acid and its derivatives: A pharmacological overview”. Basic and Clinical Pharmacology and Toxicology 110 (2012): 122-132.
  58. Mantelingu K., et al. “Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: Probed by surface-enhanced Raman spectroscopy”. The Journal of Physical Chemistry B 17 (2017): 4527-4533.
  59. Balasubramanyam K., et al. “Small molecule modulators of histone acetyltransferase p300”. Journal of Biological Chemistry21 (2003): 19134-19140.
  60. Balasubramanyam K., et al. “Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription”. Journal of Biological Chemistry49 (2004): 51163-51171.
  61. Campbell RM and Tummino PJ. “Cancer epigenetics drug discovery and development: the challenge of hitting the mark”. Journal of Clinical Investigation 1 (2014): 64-69.
  62. Sneeringer CJ., et al. “Coordinated activities of wild-hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas”. Proceedings of the National Academy of Sciences of the United States of America 49 (2010): 20980-20985.
  63. Huggins J., et al. “Antiviral Drug Therapy of Filovirus Infections: S‐Adenosylhomocysteine Hydrolase Inhibitors Inhibit Ebola Virus in Vitro and in a Lethal Mouse Model”. The Journal of Infectious Diseases 179 (1999): S24.
  64. Fiskus W., et al. “Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells”. Blood 13 (2009): 2733-2743.
  65. Sun F., et al. “Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells”. Molecular Cancer Therapeutics 12 (2009): 3191-3202.
  66. Bradley WD., et al. “EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation”. Chemistry and Biology 11 (2014): 1463-1475.
  67. Jang MK., et al. “The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription”. Molecular Cell 19 (2005): 523-
  68. Maruyama T., et al. “Mammalian bromodomain protein, Brd4, interacts with replication factor C and inhibits progression to S phase”. Molecular and Cellular Biology 22 (2002): 6509-6520.
  69. French CA. “NUT Midline Carcinoma”. Cancer Genetics and Cytogenetics 1 (2010): 16-20.
  70. Borbely G., et al. “Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells”. Oncotarget 32 (2015): 33623-33635.
  71. Wang WT and Chen YQ. “Circulating microRNA in cancer: from detection to therapy”. Journal of Hematology and Oncology 1 (2014): 86.
  72. Bartel, DP. “MicroRNAs“. Cell2 (2014): 281-297.
  73. Lai EC. “MicroRNAs are complementary to 3′UTR motifs that mediate negative post-transcriptional regulation”. Nature Genetics 30 (2002): 363-364.
  74. Jody C., et al. “Epigenetics and MicroRNAs”. Pediatric Research 61 (2002): 24R-
  75. Valeri N., et al. “MicroRNA-135b promoter cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer”. Cancer Cell4 (2014) 469-483.
  76. Campbell K and Booth SA. “MicroRNA in neurodegenerative drug discovery: the way forward?” Expert Opinion Drug Discovery1 (2015).
  77. Huan-Huan Sha., et al. “MiR-138: A promising therapeutic target for cancer”. Tumor Biology4 (2017).
  78. Nebbioso A., et al. “Trials with 'epigenetic' drugs: an update”. Molecular Oncology6 (2012): 657-682.
  79. Berkley E Gryder., et al. “Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed”. Future Medicinal Chemistry4 (2012): 505-524.
  80. Sarkar S., et al. “Cancer development, progression, and therapy: an epigenetic overview”. International Journal of Molecular Sciences 14 (2013): 21087-21113.
  81. Jahangeer S., et al. “Adrenergic receptor induction in HeLa cells: synergistic effect of 5-azacytidine and butyrate”. Biochemical and Biophysical Research Communications 108 (1982): 1434-1440.
  82. Karpf AR., et al. “Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2 -deoxycytidine”. Molecular Pharmacology 59 (2001): 751-757.
  83. Sarkar S., et al. “Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy”. Epigenomics 5 (2013): 87.
  84. Yang X., et al. “Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells”. Cancer Research 61 (2001): 7025-7029.
  85. Yamashita K., et al. “Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma”. Cancer Cell 2 (2002): 485-495.
  86. Angel R de Lera and Ganesan “Epigenetic polypharmacology: from combination therapy to multitargeted drugs”. Clinical Epigenetics 8.1 (2018): 1
  87. Cheng-Jung Lai., et al. “CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity”. Cancer Research 9 (2010): 3647-3656.
  88. Thomas J Galloway., et al. “A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma”. Clinical Cancer Research 7 (2015) 1566-1573.
  89. Wang WT and Chen YQ. “Circulating microRNA in cancer: from detection to therapy”. Journal of Hematology and Oncology 1 (2014): 86.
  90. David F Tough., et al. “Epigenetic drug discovery: breaking through the immune barrier”. Nature Reviews Drug Discovery (2016).
  91. Sigalotti L., et al. “Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications”. Journal of Cell Physiology2 (2007): 330-344.
  92. Gul S. “Epigenetic assays for chemical biology and drug discovery”. Clinical Epigenetics 9 (2017): 41.
  93. Noël J-M Raynal., et al. “Repositioning fda-approved drugs in combination with epigenetic drugs to reprogram colon cancer epigenome". MLL Cancer Therapy (2016).
  94. Huang Z., et al. “HEMD: An Integrated Tool of Human Epigenetic Enzymes and Chemical Modulators for Therapeutics”. PLoS ONE 6 (2012): e39917.
  95. Qi Y., et al. “HEDD: the human epigenetic drug database”. Database: The Journal of Biological Databases and Curation (2016): baw159.
  96. Jones PA and Martienssen R. “A blueprint for a Human Epigenome Project: the AACR Human Epigenome Workshop”. Cancer Research 24 (2005): 11241-11246.
  97. Rodenhiser D and Mann M. “Epigenetics and human disease: translating basic biology into clinical applications”. CMAJ: Canadian Medical Association Journal 3 (2006): 341-348.

 

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Citation

Citation: Roberto Verna., et al. “Strategic Therapies with Epigenetic Drugs: A Review". Acta Scientific Pharmaceutical Sciences 4.10 (2020): 100-119.




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