HDAC INHIBITOR AND ITS EEFICACY IN CANCER

by Selleckchem | Mar 19 2012

Introduction: Inhibition of Histone deacetylase function

Checks and balances are key terms used when describing the modulation of the cell growth pathways and quality assurance mechanisms [1]. Verification of every stage in the process is checked for completion and there should be a balance between cell growth & cell death depending on the circumstances. Balance is maintained via the signaling pathways, which require a chemical change to transmit their signals down the line. Typically, this is the phosphorylation of the tyrosine kinase-binding domain. This domain is found in the large super family of protein kinases that dominate the regulation of cell growth [2;3]. However, phosphorylation is not the only mechanism of activation, acetylation can also be utilized and this is where the histone deacetylase proteins comes into play. HDAC´s have been classified into four categories of which class 1 HDAC´s are primarily located in the nucleus, and are linked to transcriptional activation.. Class 2 HDAC´s carry signals from cytosole into the nucleus were transcriptional activities are triggered. Classes 3 and 4 are not well defined and have not been associated with cancer chemotherapy or any metabolic disorders to date [4;5]. Since HDAC´s of the class one and two are so important in the transcription activities, they represent a potential target for chemotherapeutic action and significant research has been applied to locating a suitable HDAC pathway inhibitor [6;7].

Forms of HDAC inhibitors

HDAC inhibition was first achieved pre-clinically with hydroximate derivatives that were established to inhibited all isoforms of class 1 & 2 HDAC´s. Subsequently cyclic peptides, aliphatic acids and benzamide derivatives have demonstrated significant activity in relation to HDAC´s. The HDAC inhibitor mechanism depends on the molecular structure of the inhibitor molecule but generally the inhibition of the deacetylation of proteins leads to an accumulation of the acetylated forms which subsequently alters their basic functions and upsets the balance in the cell [8;9]. Determination of the effects of HDAC inhibitors can be tracked with HDAC inhibitor assays determining absolute amounts of inhibitor in relation to HDAC activity as determined a specific HDAC assay. The HDAC activity assay is freely available from a variety of sources and is considered a reliable technique [10].

HDAC’s Clinical status

HDAC selective inhibitors are relatively new in the chemotherapeutic treatment of metabolic disorders but literature is focused on HDAC’s in cancer to the exclusion of nearly everything else [11]. The first HDAC inhibitor drug to gain notices was the molecule previously known as Vorinostat [12]. This molecule was extensively investigated pre-clinically demonstrating classic anti tumor activity in T-Cell lymphoma for which the FDA subsequently approved it in the USA. However, Vorinostat (SAHA) is not a HDAC specific inhibitor [13] and several other molecule have been introduced with a higher degree of specificity towards class 1 or class 2 HDAC’s [14;15]. Entinostat is such a HDAC kinase inhibitor and is being used in wide variety of cancer types including Breast, lung and Hodgkin’s lymphoma type cancers. A similar derivative is Panobinostat manufactured by Novartis and developed to phase II level in various forms of leukemia and lymphoma. While results are not available publically the pharmaceutical firm Novartis has release a press statement the this molecule will be moving into phase III with Hodgkin’s Lymphoma and myeloid leukemia, which indicates to promising results for this molecule. Another HDAC antagonist demonstrated good activity and strong potency in the clinical setting is Belinostat which has induced a high degree of disease stabilization of forms of mesothelioma at the phase II level. Further HDAC inhibitor in clinical trials include Savicol (phase II), Baceca (phase II), MS-275 (phase II) and LBH589 (phase I) [16]. The researcher interested in this work can buy HDAC inhibitors for reasonable prices from a multitude of suppliers.

References

1. Mork CN, Faller DV et al. A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors. Curr Pharm Des 2005; 11(9):1091-1104.

2. Kramer OH, Gottlicher M et al. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab 2001; 12(7):294-300.

3. Ouaissi M, Ouaissi A. Histone deacetylase enzymes as potential drug targets in cancer and parasitic diseases. J Biomed Biotechnol 2006; 2006(2):13474.

4. Weichert W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett 2009; 280(2):168-176.

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

6. Weidle UH, Grossmann A. Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment. Anticancer Res 2000; 20(3A):1471-1485.

7. Wiech NL, Fisher JF et al. Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders. Curr Top Med Chem 2009; 9(3):257-271.

8. Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res 2011; 3(2):166-179.

9. Xu WS, Parmigiani RB et al. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 2007; 26(37):5541-5552.

10. Hauser AT, Jung M et al. Assays for histone deacetylases. Curr Top Med Chem 2009; 9(3):227-234.

11. Marsoni S, Damia G et al. A work in progress: the clinical development of histone deacetylase inhibitors. Epigenetics 2008; 3(3):164-171.

12. Venugopal B, Evans TR. Developing histone deacetylase inhibitors as anti-cancer therapeutics. Curr Med Chem 2011; 18(11):1658-1671.

13. Wise LD, Turner KJ et al. Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Birth Defects Res B Dev Reprod Toxicol 2007; 80(1):57-68.

14. Yoshida M, Matsuyama A et al. From discovery to the coming generation of histone deacetylase inhibitors. Curr Med Chem 2003; 10(22):2351-2358.

15. Drummond DC, Noble CO et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005; 45:495-528.

16. Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009; 280(2):233-241.