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HDAC INHIBITORS – CANCERS AND BEYOND

Introduction: Histone deacetylases

Cellular growth is regulated via many different mechanisms in the mammalian species, depending on the mechanism or pathway that is triggered to what effect is seen in the body. One of these regulatory compounds is called histone deacetylase or abbreviated to HDAC. As it name indicates this enzymes function is to remove an acetyl group from a target, this can be either a protein or a non-protein molecule. The removal of the acetyl group results in a conformational change in the target protein that triggers further signaling down a “pathway” that results in the induction or inhibition of carious growth related activities in the cell. HDAC is not a single protein but exists in 18 different isoforms which are classified into four groups based on their activity and physical nature. Located in the nucleus are HDAC’s 1, 2, 3 & 8[1;2] responsible for mostly transcription activities. In the cytosole are the HDAC’s 4, 5, 7 & 9 [1], these transmit signals between extracellular sources and the nucleus. HDAC 11 and HDAC’s 6 & 10 are located in between cytosole and nucleus, their function varies [4;5].

The function of HDAC´s is very simple; upon receipt of a transcription signal remove the acetyl group from the designated proteins. In contrast, histone transferases will act contrary to HDAC´s and acetylate designated proteins, this act´s much like a switch of on / off for protein activities [3;6]. Class-1 HDAC’s have demonstrated activity in proliferation and in the regulation of specific gene sequences determined with the use of murine knockout models [7]. Specific target suggested are in the skeletal and neuronal areas of development since HDAC1 knock mice do not survive to birth, demonstrating serve growth deformities and abnormalities [8]. HDAC2 is not well understood yet but indications are that they play a significant role in the proliferation and differentiation in cardiac development through an interaction with the homeodomain-only protein (HOP)[9-12] Class-II HDAC’s have been demonstrated to have functionality in the formation of the skeleton and skeleton muscle fibres, in the development of cardiac muscles and in cardiac stress [13-15]. Class III HDAC’s are also known as sirtuin’s and have been linked to aging, apoptosis and stress resistance [16;17]

In terms of physiology the HDAC’s have such a broad role that the potential inhibition of any one of the many isoforms would have a significant effect on the function of the organism in which it is used, theoretically. However, HDAC inhibitors seem to work reasonable well clinically.

Inhibition of Histone deacetylase:

Using a HDAC pathway inhibitor it is possible to selectively inhibit class 1, II and IV HDAC’s but not the class III HDAC’s. The HDAC inhibitor mechanism of action for the class I, II and IV HDAC’s is dependent on the skeletal structure of the inhibitor molecule but essentially the hydroxamic acid, benzamide, or aliphatic derivatives bind to the Zinc molecule in the tail of the binding domain blocking its action.  HDAC inhibition has been demonstrated in a range of molecules such as the hydroxamate derivatives SAHA, LBH589, PXD101, ITF2357, PCI24781 (class 1&II inhibitors), benzamide derivatives MS275&MGCD0103 (HDAC1,2,3 & class 1 respectively) and the Aliphatic acid derivatives phenylbutyrate, valproic acid, AN-9, Baceca & Savicol. To determine pharmacokinetic and pharmacodynamic properties of HDAC inhibitors there are several HDAC inhibitor assays reported in literature that permit the analysis of blood and tissue [18-22]. For the HDAC activity assays it is normal to use the Sulforhodamine B colorimetric (SRB) cytotoxic assay[23] or the MTT  HDAC assay.

Pre-clinical and Clinical status of HDAC inhibitors:

Research into the role of HDAC’s in the physiological process is extensive and HDAC inhibitor drugs are freely available from a variety of suppliers. Researchers can buy HDAC inhibitors for quite reasonable prices for significant amounts. Since the discovery of the link between HDAC – Cancer some inhibitors have been tested to phase III levels

Pre-clinically there is a concerted effort to find the HDAC kinase inhibitor that is the a HDAC selective inhibitor for any of the HDAC many isoforms. HDAC specific inhibitors for HDAC1 or HDAC2 have been discovered along with specific HDAC antagonists for HDAC4 and 5.

Some of the more significant HDAC inhibitor in clinical trials are: Panobinostat (phase III) in T cell lymphoma, The Magnesium salt of Valporic acid (phase III) in cervical and ovarian and Belinostat (phase II) in relapsed ovarian. Vorinostat has been studied in breast cancer in combination with Capecitabine but the status of this trial is unknown at the moment. Entinostat (MS275) is under investigation in a variety of conditions at phase II while SB939 is being investigated in prostate cancer at phase II. There are too many to list but confirms that HDAC inhibitors represent the future of some areas cancer treatment.

References

    1.    Martin M, Kettmann R et al. Class IIa histone deacetylases: regulating the regulators. Oncogene 2007; 26(37):5450-5467.

    2.    Witt O, Deubzer HE et al. HDAC family: What are the cancer relevant targets? Cancer Lett 2009; 277(1):8-21.

    3.    Jurkin J, Zupkovitz G et al. Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle 2011; 10(3):406-412.

    4.    Codd R, Braich N et al. Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 2009; 41(4):736-739.

    5.    Rajendran P, Williams DE et al. Metabolism as a key to histone deacetylase inhibition. Crit Rev Biochem Mol Biol 2011; 46(3):181-199.

    6.    Brunmeir R, Lagger S et al. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol 2009; 53(2-3):275-289.

    7.    Lagger G, O'Carroll D et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 2002; 21(11):2672-2681.

    8.    Lagger S, Meunier D et al. Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans. EMBO J 2010; 29(23):3992-4007.

    9.    Liu F, Levin MD et al. Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Mol Cell Cardiol 2008; 45(6):715-723.

  10.    Kee HJ, Sohn IS et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 2006; 113(1):51-59.

  11.    Kook H, Lepore JJ et al. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest 2003; 112(6):863-871.

  12.    Hamamori Y, Schneider MD. HATs off to Hop: recruitment of a class I histone deacetylase incriminates a novel transcriptional pathway that opposes cardiac hypertrophy. J Clin Invest 2003; 112(6):824-826.

  13.    Chabane N, Li X et al. HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity. J Cell Biochem 2009; 106(3):453-463.

  14.    Menegola E, Di RF et al. Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol 2005; 74(5):392-398.

  15.    Di RF, Broccia ML et al. Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate. Toxicol Sci 2007; 98(2):582-588.

  16.    North BJ, Marshall BL et al. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 2003; 11(2):437-444.

  17.    North BJ, Verdin E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol 2004; 5(5):224.

  18.    Yeo P, Xin L et al. Development and validation of high-performance liquid chromatography-tandem mass spectrometry assay for 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide, a novel HDAC inhibitor, in mouse plasma for pharmacokinetic studies. Biomed Chromatogr 2007; 21(2):184-189.

  19.    Saha S, Singh SB et al. High performance liquid chromatographic method for residue determination of sulfosulfuron. J Environ Sci Health B 2003; 38(3):337-347.

  20.    Du L, Musson DG et al. High turbulence liquid chromatography online extraction and tandem mass spectrometry for the simultaneous determination of suberoylanilide hydroxamic acid and its two metabolites in human serum. Rapid Commun Mass Spectrom 2005; 19(13):1779-1787.

  21.    Otaegui D, Rodriguez-Gascon A et al. Pharmacokinetics and tissue distribution of Kendine 91, a novel histone deacetylase inhibitor, in mice. Cancer Chemother Pharmacol 2009; 64(1):153-159.

  22.    Patel K, Guichard SM et al. Simultaneous determination of decitabine and vorinostat (Suberoylanalide hydroxamic acid, SAHA) by liquid chromatography tandem mass spectrometry for clinical studies. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 863(1):19-25.

  23.    Curtin M, Glaser K. Histone deacetylase inhibitors: the Abbott experience. Curr Med Chem 2003; 10(22):2373-2392.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1030 Panobinostat (LBH589) Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Panobinostat (LBH589) induces autophagy and apoptosis. Panobinostat effectively disrupts HIV latency in vivo. Phase 3. (325) (12)
S1085 Belinostat (PXD101) Belinostat (PXD101, NSC726630, PX-105684) is a novel HDAC inhibitor with IC50 of 27 nM in a cell-free assay, with activity demonstrated in cisplatin-resistant tumors. Belinostat (PXD101) induces autophagy. (79) (8)
S2170 Givinostat (ITF2357) Givinostat (ITF2357) is a potent HDAC inhibitor for maize HD2, HD1B and HD1A with IC50 of 10 nM, 7.5 nM and 16 nM in cell-free assays. Phase 2. (27) (4)
S1090 Abexinostat (PCI-24781) Abexinostat (PCI-24781, CRA-024781) is a novel pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM, modest potent to HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Phase 1/2. (18) (3)
S1053 Entinostat (MS-275) Entinostat (MS-275, SNDX-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10. Entinostat induces autophagy and apoptosis. Phase 3. (371) (14)
S1122 Mocetinostat (MGCD0103) Mocetinostat (MGCD0103, MG0103) is a potent HDAC inhibitor with most potency for HDAC1 with IC50 of 0.15 μM in a cell-free assay, 2- to 10- fold selectivity against HDAC2, 3, and 11, and no activity to HDAC4, 5, 6, 7, and 8. Mocetinostat (MGCD0103) induces apoptosis and autophagy. Phase 2. (93) (6)

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