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Anticancer therapy: Histone Deacetylase Inhibitors

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  1. Anticancer therapy: Histone Deacetylase Inhibitors Afsha Rais

  2. Histones are so cool! • 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

  3. Introduction to HDAC • 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

  4. www.pharmadd.com/.../graphs/HDAC%20Inhib_lg.gif

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

  6. Cancer and HDAC?! • 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

  7. HDAC Biology • Histone acetylation – attachment of acetyl groups (-COCH3) 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.

  8. HDAC inhibitors • 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

  9. The short chain fatty acids • 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.

  10. Hydroxamic acid • First compound to be identified as HDAC inhibitors • suberoyl anilide hydroxamic acid (SAHA) • helped define the model pharmacophore for HDAC inhibitors

  11. SuberoylanilideHydroxamic Acid (SAHA)

  12. Trichostatin A (TSA) Hydroxamic acid Reversible inhibitor of Histone deacetylase Induce cell cycle arrest at G1, apoptosis, and cellular differentiation Has some uses as anti-cancer drug

  13. Cyclic tetrapeptides • Apicidin • Ethyl ketone component • Depsipeptide • Modulate the expression of genes • Trapoxin

  14. Benzamides • 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

  15. www.ifom-ieo-campus.it/research/chiocca.php

  16. Summary • 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.

  17. Future • 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.

  18. References • Kouraklis, Author's first name initialG., & Theocharis, S. (2002). Histone Deacetylase Inhibitors and Anticancer Therapy. Curr. Med Chem - Anti-Cancer Agents. 2, 477-484. • Fang, J (2005).Histone deacetylase inhibitors, anticancerous mechanism and therapy for gastrointestinal cancers. Journal of Gastroenterology and Hepatology. 20, 988-994. • Miller, T., Witter, D., & Belvedere, S. (2003). Histone Deacetylase Inhibitors. Journal of Medicinal Chemistry. 46, 5097-5116. • http://www.nlm.nih.gov/medlineplus.html • 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, 2216-2219. • Campbell, N., & Reece, J. (2002). Biology.San Francisco: Benjamin Cummings. • www.metahistory.org/images/Nucleosome.jpg