Histone Deacetylation

Danielle Herrmann2013 Doctor of Pharmacy Candidate

University of Kansas School of PharmacyMidwest 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

• They contain long N-terminal extensions that undergo post translational modifications including: acetylation, methylation, and phosphorylation

Why is this important?• Histones can be modified in many ways• Two families of enzymes that play a big role in these

modifications: histone acetyltransferases (HATs) and histone deacetylases (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 histone acetylation are being developed and looked into for possible avenues to treat certain types of cancer

•

• 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

HDACs

• Three type of HDAC’s class 1 – HDAC1– HDAC2– HDAC3

• HDAC8• HDAC class 2• HDAC class 3

Controlling HDAC activity

• Accumulate in higher molecular weight complexes

• Mechanisms – Enzymatic activity– Functional activity

• Biological functions dependent on enzymatic activity

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

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

http://jco.ascopubs.org/content/29/9/1198/F1.large.jpg

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.