Afsha Rais

 In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.  Histones have a high proportion of positively charged amino acids (lysine and arginine) which bind tightly to the negatively charged DNA.  Four core histones H2A, H2B, H3, and H4 serve to wrap DNA into nucleosomes.  Nucleosomes is the repeating pattern of 8 histone proteins along the length of the chromatin structure, with each octet associated with 146 basepairs of DNA  The linker histone H1 role

 Dimethyl sulfoxide (DMSO) › Terminal differentiation of murine erythroleukemia cells › Interest in Histone Deacetylase (HDAC) inhibitors › Chromatin remodeling  SAHA made it!! › Treat rare cancer cutaneous T-cell lymphoma (CTCL)  Antitumor action of compounds undergoing clinical trials

The main pharmacological application for HDAC inhibitors is the treatment of cancer.

 How does cancer occur?  Transcription therapy  treatment for cancer  2 enzymes in the cell › Histone acetyltransferase (HAT) › Histone deacetylase (HDAC)  Histone deacetylase inhibitors (HDI)  Importance

 Histone acetylation – attachment of acetyl groups (-COCH 3 ) to certain amino acids of histone proteins; Histone deacetylation – the removal of acetyl groups.  HDACs have many functions such as regulation of gene transcription, regulation of gene expression by deacetylating transcription factors, gene slicing, differentiation, and participation in cell cycle regulation.

HDAC Classes Class I HDAC -1, -2, -3, -8 Class IIClass IIa HDAC -4, -5, -7, -9 Class IIbHDAC -6, -10Class III SIRT -1, -2, -3, -4, -5, -6, -7 Class IVHDAC 11

 Class of compounds that interfere with the function of histone deacetylase  4 classes of HDAC inhibitors › A short-chain fatty acid › Hydroxamic acid › Cyclic tetrapeptides › Benzamides

 Phenylbutyrate › One of the first HDAC inhibitors to be tested in patients  Valporic acid › a histone deacetylase inhibitor (HDACI), in vitro induces differentiation of promyelocyte leukemia cell and proliferation arrest and apoptosis of various leukemia cell lines.

 First compound to be identified as HDAC inhibitors  suberoyl anilide hydroxamic acid (SAHA)  helped define the model pharmacophore for HDAC inhibitors

 Hydroxamic acid  Reversible inhibitor of Histone deacetylase  Induce cell cycle arrest at G1, apoptosis, and cellular differentiation  Has some uses as anti-cancer drug

 Apicidin  Ethyl ketone component  Depsipeptide  Modulate the expression of genes  Trapoxin

 Two drugs undergoing clinical trial › MS-275  A substance that is being studied in the treatment of cancers of the blood  Mice experiment and result › CI-994  Mechanism of antitumor activity unclear  Causes accumulation of acetylated histones although is not able to inhibit HDAC activity in a direct fashion

 HDAC inhibitors induce growth arrest, differentiation, and/or apoptotic cell death in transformed cells.  This inhibition of HDAC activity leads to relaxation of the structure of chromatin. › The relaxed chromatin structure allows these genes to be expressed, which finally inhibit tumor cell growth.  Research shows that HDAC inhibitors are well tolerated can inhibit activity in tumoral cells and have efficiency in tumor regression.

 Further clinical studies are needed to define the optimal dosage and duration of therapy with HDAC inhibitors in the fight against cancer.  Additionally, more work is needed to understand the molecular basis of the HDAC inhibitors selectivity in the alteration of gene transcription, and in chromatin dynamics during malignant transformation.  Lastly, the resistance of normal cells to HDAC inhibition by these agents is also needed to be studied further.

1. Kouraklis, Author's first name initialG., & Theocharis, S. (2002). Histone Deacetylase Inhibitors and Anticancer Therapy. Curr. Med Chem - Anti-Cancer Agents. 2, Fang, J (2005).Histone deacetylase inhibitors, anticancerous mechanism and therapy for gastrointestinal cancers. Journal of Gastroenterology and Hepatology. 20, Miller, T., Witter, D., & Belvedere, S. (2003). Histone Deacetylase Inhibitors. Journal of Medicinal Chemistry. 46, Bieliauskas, A., Weerasinghe, S., & Pflum, M. (2007). Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid. Bioorganic & Medicinal Chemistry Letters. 17, Campbell, N., & Reece, J. (2002). Biology.San Francisco: Benjamin Cummings