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Histone Deacetylation

Histone Deacetylation. Danielle Herrmann 2013 Doctor of Pharmacy Candidate University of Kansas School of Pharmacy Midwest Cancer Care . Histones. Histones are proteins that act as spool for the DNA to wind around They play important roles in the regulation of gene expression

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Histone Deacetylation

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  1. Histone Deacetylation Danielle Herrmann 2013 Doctor of Pharmacy Candidate University of Kansas School of Pharmacy Midwest Cancer Care

  2. Histones • Histones are proteins that act as spool for the DNA to wind around • They play important roles in the regulation of gene expression • They contain long N-terminal extensions that undergo post translational modifications including: acetylation, methylation, and phosphorylation

  3. Why is this important? • Histones can be modified in many ways • Two families of enzymes that play a big role in these modifications: histoneacetyltransferases (HATs) and histonedeacetylases (HDACs) • These enzymes are key in important cellular processes including transcription, DNA replication, and cell cycle progression • Because of these roles; medications that inhibit these enzymes and affect histoneacetylation are being developed and looked into for possible avenues to treat certain types of cancer

  4. Over expression of HDACs is seen in many type of cancer cells, especially lymphomas and colon cancers • Histone deacetylases (HDACs) work by removing acetyl groups on the chromatin resulting in a condensed structure and inhibition of transcription • Inhibition of HDAC increases the amount of acetyl groups on the histone and allows the chromatin structure to open and transcription to occur • This inhibits the cell cycle, induces apoptosis and allows for differentiation

  5. HDACs • Three type of HDAC’s class 1 • HDAC1 • HDAC2 • HDAC3 • HDAC8 • HDAC class 2 • HDAC class 3

  6. Controlling HDAC activity • Accumulate in higher molecular weight complexes • Mechanisms • Enzymatic activity • Functional activity • Biological functions dependent on enzymatic activity

  7. Drugs in clinical trials • 5 classes of HDACi’s • Short chain fatty acids- butyric acid, Pivanex • Hydroxamic Acids- vorinostat, TSA • Electrophylic ketones • Aminobenzamides- MS-275 now in clinical trials to treat melanoma • Natural cyclic peptides- romidepsin and apicidin

  8. Drugs on the market • Vorinostat (suberoylanilide hydroxamic acid) • High potency, low toxicity, and excellent stability • Progressive, persistent or recurrent cutaneous T-cell lymphoma • Inhibits HDAC1, HDAC2, HDAC3, and HDAC6 enzymes • 25% efficacious in CTCL • Not effective in solid tumors used alone • Time to response between 3.9-21.5 weeks • Thrombocytopenia, Fatigue and Diarrhea was among the most widely seen adverse effect

  9. References • Akilov, Oleg. "Therapeutic Advances in Cutaneous T-Cell Lymphoma ." Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 16. (2011): n. pag. Web. 13 Jun 2011. • Duvic, Madeleine. "Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)." American Society of Hematology 10. (2007): 31-39. Web. 8 Jun 2011. • Gallinari, Paola, and Stefania Di Marco. "HDACs, histone deacetylation and gene transcription; from molecular biology to cancer therapeutics." Cell Research 17. (2007): 195-211. Web. 8 Jun 2011. • "Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs." American Journal of Translational Research 3. (2010): 166-179. Web. 8 Jun 2011.

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