Anticancer therapy: Histone Deacetylase Inhibitors

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Anticancer therapy Histone Deacetylase Inhibitors

• Afsha Rais

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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

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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

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www.pharmadd.com/.../graphs/HDAC20Inhib_lg.gif
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The main pharmacological application for HDAC
inhibitors is the treatment of cancer.
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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

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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.

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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

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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.

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Hydroxamic acid

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

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Suberoylanilide Hydroxamic Acid (SAHA)
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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

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Cyclic tetrapeptides

• Apicidin
• Ethyl ketone component
• Depsipeptide
• Modulate the expression of genes
• Trapoxin

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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

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

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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.

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References

1. Kouraklis, Author's first name initialG.,
   Theocharis, S. (2002). Histone Deacetylase
   Inhibitors and Anticancer Therapy. Curr. Med Chem
   - Anti-Cancer Agents. 2, 477-484.
2. Fang, J (2005).Histone deacetylase inhibitors,
   anticancerous mechanism and therapy for
   gastrointestinal cancers. Journal of
   Gastroenterology and Hepatology. 20, 988-994.
3. Miller, T., Witter, D., Belvedere, S. (2003).
   Histone Deacetylase Inhibitors. Journal of
   Medicinal Chemistry. 46, 5097-5116.
4. http//www.nlm.nih.gov/medlineplus.html
5. 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.
6. Campbell, N., Reece, J. (2002). Biology.San
   Francisco Benjamin Cummings.
7. www.metahistory.org/images/Nucleosome.jpg