Histone deacetylase inhibitor

Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases.

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are being investigated as possible treatments for cancers,[1][2] parasitic[3] and inflammatory diseases.[4]

Cellular biochemistry/pharmacology

To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active euchromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.[5][6][7] The open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes.[7]

The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone deacetylase inhibitors exert their anti-tumour effects via the induction of expression changes of oncogenes or tumour suppressor, through modulating the acetylation/deactylation of histones and/or non-histone proteins such as transcription factors.[8] Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetylated nucleosome core histones in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Acetylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA1 but may repress transcriptional activity of others including T cell factor and the co-activator ACTR. Recent studies [...] have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors.[9] Conservation of the acetylated ER-alpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents."[10]

HDAC classification

Based on their homology of accessory domains to yeast histone deacetylases, the 18 currently known human histone deacetylases are classified into four groups (I-IV):[11]

  • Class I, which includes HDAC1, -2, -3 and -8 are related to yeast RPD3 gene;
  • Class IIA, which includes HDAC4, -5, -7 and -9; Class IIB -6, and -10 are related to yeast Hda1 gene;
  • Class III, also known as the sirtuins are related to the Sir2 gene and include SIRT1-7
  • Class IV, which contains only HDAC11 has features of both Class I and II.

HDI classification

The "classical" HDIs act exclusively on Class I, II and Class IV HDACs by binding to the zinc-containing catalytic domain of the HDACs. These classical HDIs can be classified into several groupings named according to the chemical moiety that binds to the zinc ion (except cyclic tetrapeptides which bind to the zinc ion with a thiol group). Some examples in decreasing order of the typical zinc binding affinity:[12]

  1. hydroxamic acids (or hydroxamates), such as trichostatin A,
  2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
  3. benzamides,
  4. electrophilic ketones, and
  5. the aliphatic acid compounds such as phenylbutyrate and valproic acid.

"Second-generation" HDIs include the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589); and the benzamides : entinostat (MS-275), tacedinaline (CI994), and mocetinostat (MGCD0103).[13][14]

The sirtuin Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide, as well as derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphthaldehydes.[15]

Additional functions

HDIs should not be considered to act solely as enzyme inhibitors of HDACs. A large variety of nonhistone transcription factors and transcriptional co-regulators are known to be modified by acetylation. HDIs can alter the degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism. Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, MKP-1, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc.[12][16][17]

Uses

Psychiatry and neurology

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.[18] Enhancement of memory formation is increased in mice given vorinostat, or by genetic knockout of the HDAC2 gene in mice.[19] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.[20]

Pre Clinical Research – HDI therapy for the treatment of depression

Recent research into the causes of depression has highlighted some possible gene-environment interactions that could explain why after much research, no specific genes or loci which would indicate risk for depression have emerged.[21] Recent studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission,[22] suggesting that there could be an epigenetic component to depression that is not being addressed by current pharmacological treatments. Environmental stressors, namely traumatic stress in childhood such as maternal deprivation and early childhood abuse have been studied for their connection to a high risk of depression in adulthood. In animal models, these types of trauma have been shown to have significant effects on histone acetylation, particularly at gene loci which have known connection to behavior and mood regulation.[21][23] Current research has focused on the use of HDI therapy for depression after studies on depressed patients in the middle of a depressive episode found increased expression of HDAC2 and HDAC5 mRNA compared to controls and patients in remission.[23]

Effects on gene expression

Various HDAC inhibitors (HDI) have been studied for their connection to the regulation of mood and behavior, each having different, specific effects on the regulation of various genes. The most commonly studied genes include Brain-derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) both of which help regulate neuron growth and health, whose down regulation can be a symptom of depression.[23] Multiple studies have shown that treatment with an HDI helps to up regulate expression of BDNF: valproic acid (commonly used to treat epilepsy and bipolar disorder)[22] as well as sodium butyrate[23] both increased expression of BDNF in animal models of depression. One study which traced GDNF levels in the ventral striatum found increased gene expression upon treatment with SAHA.[22]

Effects on depressive behaviors

Pre-clinical research on the use of HDAC inhibitors (HDI) for the treatment of depression use rodents to model human depression. The tail suspension test (TST) and the forced swimming test (FST) measure the level of defeat in rodents— usually after treatment with chronic stress— which mirrors symptoms of human depression. Alongside tests for levels of HDAC mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine whether or not treatment with an HDI has been successful in ameliorating symptoms of depression. Studies which used SAHA or MS-275 as their treatment compound found treated animals displayed gene expression profiles similar to those treated with fluoxetine, and displayed similar anti-depressant like behavior.[21][22][23] Sodium butyrate is commonly used as a candidate for mood disorder treatment: studies using it both alone and in co-treatment with fluoxetine report subjects with increased performance on both TST and FST[22] in addition to increased expression of BDNF.[23]

Cancer treatment

Pan-HDAC inhibitors have shown anticancer potential in several in in vitro and in vivo studies, focused on Pancreatic, Esophageal squamous cell carcinoma (ESCC), Multiple myeloma, Prostate carcinoma, Gastric cancer, Leukemia, breast, Liver cancer, ovarian cancer, non-Hodgkin lymphoma and Neuroblastoma.[24] Because of the massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific HDACi treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 (panobinostat) and the BET bromodomain JQ1 compound.[25]

Inflammatory diseases

Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents.[26]

HIV/AIDS

After the successful initial round of in vitro research in January 2013, the Danish Research Council awarded the research team led by Dr. Ole Søgaard from the Danish Aarhus University Hospital the amount of $2 million to proceed with clinical trials on 15 humans. The goal is for HDAC inhibitors to flush HIV from the reservoirs it builds within the DNA of infected cells, followed by a vaccination to help the immune system to neutralize any replicating virus.[27]

One study noted the use of panobinostat, entinostat, romidepsin, and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs. Vorinostat was noted as the least potent of the HDAC inhibitors in this trial.[28] Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo.[29]

Other diseases

HDIs are also being studied as protection of heart muscle in acute myocardial infarction.[30]

References

  1. ↑ Miller TA, Witter DJ, Belvedere S (November 2003). "Histone deacetylase inhibitors". Journal of Medicinal Chemistry. 46 (24): 5097–116. doi:10.1021/jm0303094. PMID 14613312.
  2. ↑ Mwakwari SC, Patil V, Guerrant W, Oyelere AK (2010). "Macrocyclic histone deacetylase inhibitors". Current Topics in Medicinal Chemistry. 10 (14): 1423–40. doi:10.2174/156802610792232079. PMC 3144151. PMID 20536416.
  3. ↑ Patil V, Guerrant W, Chen PC, Gryder B, Benicewicz DB, Khan SI, et al. (January 2010). "Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group". Bioorganic & Medicinal Chemistry. 18 (1): 415–25. doi:10.1016/j.bmc.2009.10.042. PMC 2818366. PMID 19914074.
  4. ↑ Blanchard F, Chipoy C (February 2005). "Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?". Drug Discovery Today. 10 (3): 197–204. doi:10.1016/S1359-6446(04)03309-4. PMID 15708534.
  5. ↑ Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF (March 2003). "Histone deacetylases: unique players in shaping the epigenetic histone code". Annals of the New York Academy of Sciences. 983 (1): 84–100. Bibcode:2003NYASA.983...84T. doi:10.1111/j.1749-6632.2003.tb05964.x. PMID 12724214.
  6. ↑ Marks PA, Richon VM, Rifkind RA (August 2000). "Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells". Journal of the National Cancer Institute. 92 (15): 1210–6. doi:10.1093/jnci/92.15.1210. PMID 10922406.
  7. 1 2 Dokmanovic M, Clarke C, Marks PA (October 2007). "Histone deacetylase inhibitors: overview and perspectives". Molecular Cancer Research. 5 (10): 981–9. doi:10.1158/1541-7786.MCR-07-0324. PMID 17951399.
  8. ↑ Chueh AC, Tse JW, Tögel L, Mariadason JM (July 2015). "Mechanisms of Histone Deacetylase Inhibitor-Regulated Gene Expression in Cancer Cells". Antioxidants & Redox Signaling. 23 (1): 66–84. doi:10.1089/ars.2014.5863. PMC 4492771. PMID 24512308.
  9. ↑ Gryder BE, Rood MK, Johnson KA, Patil V, Raftery ED, Yao LP, et al. (July 2013). "Histone deacetylase inhibitors equipped with estrogen receptor modulation activity". Journal of Medicinal Chemistry. 56 (14): 5782–96. doi:10.1021/jm400467w. PMC 3812312. PMID 23786452.
  10. ↑ Vigushin DM, Coombes RC (March 2004). "Targeted histone deacetylase inhibition for cancer therapy". Current Cancer Drug Targets. 4 (2): 205–18. doi:10.2174/1568009043481560. PMID 15032670.
  11. ↑ "Histone deacetylase (HDAC) Inhibitors Database". hdacis.com. Retrieved 6 October 2015.
  12. 1 2 Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005). "Clinical development of histone deacetylase inhibitors as anticancer agents". Annual Review of Pharmacology and Toxicology. 45: 495–528. doi:10.1146/annurev.pharmtox.45.120403.095825. PMID 15822187.
  13. ↑ Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, Sanders K (September 2007). "Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group". International Journal of Cancer. 121 (5): 1138–48. doi:10.1002/ijc.22751. PMID 17455259.
  14. ↑ Acharya MR, Sparreboom A, Venitz J, Figg WD (October 2005). "Rational development of histone deacetylase inhibitors as anticancer agents: a review". Molecular Pharmacology. 68 (4): 917–32. doi:10.1124/mol.105.014167. PMID 15955865.
  15. ↑ Porcu M, Chiarugi A (February 2005). "The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension". Trends in Pharmacological Sciences. 26 (2): 94–103. doi:10.1016/j.tips.2004.12.009. PMID 15681027.
  16. ↑ Yang XJ, Seto E (August 2007). "HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention". Oncogene. 26 (37): 5310–8. doi:10.1038/sj.onc.1210599. PMID 17694074.
  17. ↑ Jeong Y, Du R, Zhu X, Yin S, Wang J, Cui H, Cao W, Lowenstein CJ (April 2014). "Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1". J Leukoc Biol. 95 (4): 651–9. doi:10.1189/jlb.1013565. PMID 24374966.
  18. ↑ Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (February 2008). "Histone deacetylase inhibitors: possible implications for neurodegenerative disorders". Expert Opinion on Investigational Drugs. 17 (2): 169–84. doi:10.1517/13543784.17.2.169. PMID 18230051.
  19. ↑ Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (May 2009). "HDAC2 negatively regulates memory formation and synaptic plasticity". Nature. 459 (7243): 55–60. Bibcode:2009Natur.459...55G. doi:10.1038/nature07925. PMC 3498958. PMID 19424149.
  20. ↑ Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (November 2008). "Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau". The Journal of Neuroscience. 28 (45): 11500–10. doi:10.1523/JNEUROSCI.3203-08.2008. PMC 2617713. PMID 18987186.
  21. 1 2 3 Schroeder M, Hillemacher T, Bleich S, Frieling H (February 2012). "The epigenetic code in depression: implications for treatment". Clinical Pharmacology and Therapeutics. 91 (2): 310–4. doi:10.1038/clpt.2011.282. PMID 22205200.
  22. 1 2 3 4 5 Fuchikami M, Yamamoto S, Morinobu S, Okada S, Yamawaki Y, Yamawaki S (January 2016). "The potential use of histone deacetylase inhibitors in the treatment of depression". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 64: 320–4. doi:10.1016/j.pnpbp.2015.03.010. PMID 25818247.
  23. 1 2 3 4 5 6 Machado-Vieira R, Ibrahim L, Zarate CA (December 2011). "Histone deacetylases and mood disorders: epigenetic programming in gene-environment interactions". CNS Neuroscience & Therapeutics. 17 (6): 699–704. doi:10.1111/j.1755-5949.2010.00203.X. PMC 3026916. PMID 20961400.
  24. ↑ Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, Giorgi FM (May 2020). "Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability". Genes. 11 (5): 556–604. doi:10.3390/genes11050556. PMC 7288346. PMID 32429325.
  25. ↑ Shahbazi J, Liu Y, Atmadibrata B, Bradner JE, Marshall GM, Lock RB, Liu T (May 2016). "The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects". Clinical Cancer Research. 22 (10): 2534–2544. doi:10.1158/1078-0432.CCR-15-1666. PMID 26733615.
  26. ↑ Adcock IM (April 2007). "HDAC inhibitors as anti-inflammatory agents". British Journal of Pharmacology. 150 (7): 829–31. doi:10.1038/sj.bjp.0707166. PMC 2013887. PMID 17325655.
  27. ↑ Gayomali, Chris (April 29, 2013). "Breakthrough: Is an HIV cure just a few months away?". The Week. The Week Publications. Retrieved September 12, 2013.
  28. ↑ Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sékaly RP, Lewin SR (2014). "Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy". PLoS Pathogens. 10 (11): e1004473. doi:10.1371/journal.ppat.1004473. PMC 4231123. PMID 25393648.
  29. ↑ Wei DG, Chiang V, Fyne E, Balakrishnan M, Barnes T, Graupe M, Hesselgesser J, Irrinki A, Murry JP, Stepan G, Stray KM, Tsai A, Yu H, Spindler J, Kearney M, Spina CA, McMahon D, Lalezari J, Sloan D, Mellors J, Geleziunas R, Cihlar T (April 2014). "Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing". PLoS Pathogens. 10 (4): e1004071. doi:10.1371/journal.ppat.1004071. PMC 3983056. PMID 24722454.
  30. ↑ Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, Epstein JA, Gruber PJ (October 2008). "Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice". FASEB Journal. 22 (10): 3549–60. doi:10.1096/fj.08-108548. PMC 2537432. PMID 18606865.
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