Histone deacetylase inhibitors: pharmacotherapeutic implications as epigenetic modifier
Keywords:
Epigenetics, Histone deacetylase inhibitors, VorinostatAbstract
Epigenetic modifications such as acetylation and deacetylation of histone proteins play a decisive role in transcriptional alteration and expression of genes. Acetylation is catalysed by the histone acetyl transferases enzymes and activates expression of genes by converting chromatin into a less compact, transcriptionally active state. Histone deacetylases enzymes catalyze deacetylation that condenses chromatin into a closed structure .Consequently transcriptional factors are unable to access DNA and gene expression is suppressed. Balanced activity of HATs and HDACS is essential for normal gene expression. Increased HDAC activity can lead to imbalance in protein acetylation resulting in hypoacetylation, tight chromatin structure and suppression of various genes. This aberrant suppression of genes is the hallmark of several malignant and other diseases including neurodegenerative disorders. Histone Deacetylase Inhibitors (HDACIs) have potential to restore the balance of histone acetylation that reverses the silencing of pathological genes. Thus HDACIs modify expression of genes without affecting sequence of DNA and act as epigenetic modifiers. Vorinostat and romidepsin are FDA approved HDACIs. Valproic acid, belinostat and many others are in different phases of clinical trials. This review article explores the target based epigenetic mechanisms as well as existing and potential therapeutic role of HDACIs in various malignant and non-malignant diseases. Data sources were articles published in medical journals and bibliographic database Medline.
References
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3.
Riggs AD, Russo VEA, Martienssen RA. Epigenetic mechanisms of gene regulation. Plainview. New York, NY: Cold Spring Harbor Laboratory Press; 1996: 7.
Weil PA. DNA organization, replication and repair. Murray RK, Rodwell VW, Bender DA, Botham KM, Kannelly PJ, Weil PA, editors. Harper’s Biochemistry. 28th ed. New York. McGraw-Hill; 2009: 35(312-314).
Gregory PD, Wagner K, Hor ZW. Histone acetylation and chromatin remodeling. Exp cell Res. 2001;265:195-202.
Barnes PJ, Adcock IM, Ito k. Histone acetylation and deacetylation: Importance in inflammatory lung diseases. Eur Respir J. 2005;25(3):553.
Dokmanovic M, Clarke C, Marks PA. Histone Deacetylase Inhibitors: Overview & Perspectives. Mol Cancer Res 2007;5:982-983.
Vanlint C, Emiliani S, Verdin E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr. 1996;5:245 – 53.
Delcuve GP, Khan DH, Davie JR. Role of HDACIs in Epigenetic Regulation: Emerging Paradigms From Studies With Inhibitors. Clini Epigenetics. 2012;12;4(1):5.
Spange S, Wagner T, Heinzel T, Kramer O. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009;41:185-98.
Glaser KB. HDAC inhibitors: Clinical update & mechanism based potential. Biochem Phamacol. 2007;(5):659-71.
Ververis K, Hiong A, Karagiannis TC, Licciardi PV. Histone deacetylase inhibitors: Multitargeted anticancer agents. Biologics. 2013;7:47-60 .
Beckers T, Burkhardt C, Wieland H. "Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group". Int. J. Cancer. 2005;121(5):1138–48.
Porcu M, Chiarugi A. "The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension". Trends Pharmacol. Sci. 2005;26(2):94–103.
Glass E, Viale PH. Histone deacetylase inhibitors: Novel agents in cancer treatment. Clinical journal of oncology & nursing. 2013;17:34-40.
Kavanaugh SM, White LA, Kolesar JM. Vorinostat: A novel therapy for the treatment of cutaneous T- cell lymphoma. Am J Health Syst Pharm. 2010;67(14):1136.
Zhou W, Zhu WG: The changing face of HDAC inhibitor depsipeptide. Curr Cancer Drug Targets. 2009;9(1):91-100.
Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel ahistone deacetylase inhibitors in clinical trial as anticancer agents. Journal of hematology & oncology. 2010;3(5):1-13.
“52nd ASH Annual Meeting Presentation of initial phase II data from the Saphire Hodgking’s Lymphoma Trial with Resminostat”. 2010. Available at: http://www.businesswire.com/news/home/20101130007529/en#.UuJH7xC6bIU. Accessed 1 Dec 2010.
Viviani S, Bonfante V, Fasola C, Valagussa P, Gianni AM: Phase II study of the histone-deacetylase inhibitor ITF2357 in relapsed/refractory Hodgkin's lymphoma patients. J Clin Oncol. 2008;26(suppl);abstr8532.
Doi T, Hamaguchi T, Shirao K, Hatake K, Noguchi K, Mehta A,. Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal cancer in a phase 1 clinical trial. Int J Clin Oncol. 2013Feb;18(1):87-95.
Dinarello CA, Fossati G, Mascagn P. Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer. Mol Med. 2011;17(5-6):333–52.
Grayson DR, Kundokovic M, Sharma RP. Is there future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders?. Mol Pharmacol. 2010;77(2):126-35.
Green K, Steffan JS, Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CS. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 2009November;32(11):591-601.
Qing H, He G, Ly PT, Fox CJ, Cai F, Song W et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med. 2008;205(12):2781-9.
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001Oct18;413(6857):739-43.
Kim HJ, Rowe M, Hong JS, Chen PS, Chuang DM. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Ther. 2007;321(3):892-901.
Sheen NA, Grigoriadi S N, Alexandrovich AG, Simeonidou C, Lourbopoulos A, Polyzoidou E et al. Histone Deacetylase Inhibitor ITF2357 is neeuroprotective, improves functional recovery and induces glial apoptosis following experimental traumatic brain injury. FASEB J. 2009;23(12):4266-75.
Delsignore SJ, Amante DJ, Kin J, Stack EC, Goodrich S, Ferrante RJ. Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amayotroph Lateral Scler. 2009Apr;10(2):85-94.
Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Ferrnate RJ. Northeast ALS and National VA ALS Research Consortiums. A Phase 2 study of Sodium Phenyl butyrate in ALS. Amayotroph Lateral Scler. 2009Apr;10(2):99-106.
Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. 2006Aug8;67(3):500-1.
Gardian G, Yang L, Cleren C, Calinqasun NY, Kiveny IP, Beal MF. Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. Neuromolecular Med. 2004;5(3):225-41.
Chen PS, Peng S, Yang S, Hong JS, et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. 2006Dec;11(12):1116-25.
Kundakovick M, Chen Y, Guidotti A, Grayson DR. The reelin &GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol. Pharmacol. 2009;75(2):342-54.
Covington HE, Maze I, Laplant QC, Vialou VF, Ohnishi YN, Berton O et al. Antidepressant actions of histone deacetylase inhibitors. J Neurosci. 2009;29:11451–60.
Zhang Z, Qin X, Tong N, Zhao X, Gong Y et al. Valproic acid mediated neuroprotection in retinal ischemia injury Via Histone Deacetylase Inhibition and Transcriptional activation. Exp Eye Res. 2012;94(1):98-108.
Chung YL, Lee MY, Wang AJ, Yao LF. A Therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther. 2003;8(8):707-17.
Yalisastigui L, Archin NM, Lehrman G, Boach RJ, Margolis DM. Coaxing HIV-1from resting T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004;18(8):1101-8.
Matalon S, Palmer BE, Nold MF, Furlan A, Kassu A, Fossati G et al. The Histone Deacetylase Inhibitor ITF2357 Decreases Surface CXCR4 and CCR5 Expression on CD4+ T-Cells and Monocytes and is Superior to Valproic Acid for Latent HIV-1 Expression in vitro. J Acquir Immune Defic. 2010;54(1):1-9.
Royce SG, Dang W, Ververis K, De Sampayo N, EI Osta A, Tang ML et al. Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of airway disease. Epigenetics. 2011Dec1;6(12):1463-70.
Tamimi A, Serdarevic D, Hanania NA. The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications. Respir Med. 2012 Mar;106(3):319-28.
Mizuno S, Yasuo M, Bogaard HJ, Kraskauskas D, Natarajan R, Voelkel NF. Inhibition of deacetylase causes emphysema. AmJ Trans Res. 2011;3(5):454-67.
Larsen L, Tonnesen M, Ronn SG, Storling J, Jorgenesen S, Dinarello CA et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia. 2007Apr;50(4):779-89.
Quan W, Lim YM, Lee MS. Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells. Exp Mol Med. 2012February 29;44(2):81–8.
Cao DJ, Wang ZV, Battiprolu PK, Jiang N, Morales CR, Kong Y et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy. Proc Natl Acad Sci. U S A. 2011;108:4123–8.
Ordovas JM, Smith CE. Epigenetics & CVD: Nature reviews cardiology. 2010;7:510-9.
So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 2007;9:R28.
Bishton MJ, Harrison SJ, Martin BP, James C, Jorefsson EC, Henely KJ et al. Deciphering the molecular and biological processes that mediate histone deacetylase inhiobitor induced thrombocytopenia. Blood. 2011;117:3658-68.
Srividya Subramanian S, Bates SE, Wright JJ, Delgado IE. et al. Review Clinical Toxicities of Histone Deacetylase Inhibitors. Pharmaceuticals. 2010;3:2751-67.
Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci. U S A. 2003;100:2041–6.
Choi S, Reddy P. HDAC Inhibition and Graft Versus Host Disease. Mol Med. 2011May-Jun;17:404–16.
