Histone Deacetylase Inhibitors(HDACis) are an Exciting New Class of Medicines for Lethal Diseases

Histone Octamer is not only a protein of  the year,but a solution for the pain,suffering and death in our society caused by terminal diseases. 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341130/pdf/nihms364341.pdf

With advancing technology in the twenty-first century, we are still struggling to find the right medication that can be used as a target for lethal genetic and non-genetic diseases such as: cancer, neurodegenerative disorders and cardiac disorders.  Many of our friends, classmates, roommates and family members have been diagnosed with one type or another of these lethal diseases.  It is estimated that one in three people in the USA have a mutation. 

            Histone has been chosen as the protein of the twenty-first century for the benefits that it offers to reverse tumor cells.  This paper shares some important features that could be useful a tool in leading to eradicate this lethal disease.  The article showed that histone deacetylase is an inhibitor of cancer suppressor genes (such as p²¹) through hypoacetylation. According to this article, “over 490 clinical trials have been initiated in the last 10 years” for histone deacetylase inhibitors (HDACis) as a therapeutic alternative for cancer.  After 10 years of clinical trials, the FDA had approved 2 different HDACis : Suberoylamilide hydroxamic acid (SAHA:Vorinostat) and FK228 (romidepsin) as drugs for the treatment of cutaneous T-cell lymphoma (CTCL).  The study evaluated the results in the treatment of CTCL, and the two HDACis medications had a 50-56% success rate.  However, both of the HDACis drugs showed no effect in the treatment for solid tumors.  There were some challenges that researchers have to work on, such as the side effects of the SAHA-vorinostat and romidepsin.

            The researchers in the 490 clinical trials claimed that there are some approaches that can be applied in order to overcome the side effects of the HDACis drugs.  They suggested the following:

a)      Target preference: designing and developing drugs with high quality and selectivity for a unique molecular entity.

b)      Selective delivery: directing the medicine to the organ tissue or location of interest.  For instance, isoforms (isozymes) of HDAC: HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11.  These histone isozymes are in diverse locations and with different functions.  Isoforms selectivity would be helpful in an understanding of their locations and functions which could have tremendous clinical benefits.  There are four classes of HDAC isoforms: I, IIa, IIb, and IV.  These classes correspond with specific locations in the cell, but researchers still want to know whether there are some specific isoforms that cause cardiac toxicity or that could have therapeutic benefits for cancer? Scientists believe that in a few years some HDACis drugs will get approval from the FDA.
 

 Figure1: Discribes the factors that are influencing epigenetic mechanism

 

 

 

                 Figure2: Histone modification facilitated by enzymes acetyl transferase and histone deacetylase.

 

 

 

 

Figure3: Different classes of histone deacetylase inhibitors (HDACis)

 

 

 

 Figure4: Histone deacetylase 3 pharmacophoric model for zinc-ion-chelating inhibitor. The color blue highlights the surface of the crystal structure, gray is shown the hydrophobic tunnel and the zinc sequestering active site is shown in red.

Each histone deacetylase inhibitor pharmacophore is color-coded to show its binding within the histone deacetylase enzyme active site.

 

Histone can reverses a cancer

 

Histone Protein of interest for 21st Century

Many of the major human diseases, such as cancer, heart, neurodegenerative and psychiatric disorder correlated with modifications in the residues region of histone pos-translational modification. The residues in the N-terminal region of histone are covalentely modified by acetylation, methylation and phosphorylation. Histone is normally modified by acetylation reaction catalyzed by histone enzyme acetyltransferase (HAT). This process can make the structure of chromatin to open and facilitate transcription process. Also, the reaction can be catalyzed in the opposite direction (is reversible) by the histone enzyme deacetylase (HDAC) and it removed acetyl groups and then changed the conformation of chromatin to close, and this could possible turn genes off and thus making transcription unavailable. Some studies found that histone deacetylase enzyme plays a major role in DNA methyltransferases in silencing tumor suppressor genes. For instance, methylation of lysine 9 on histone H3 can turn genes off by changing a chromatin configuration whereas methylation of lysine 4 on histone H3 is turning genes on(Abel, 2008 and Filipe,2010).  The researchers saw histone methylation, DNA methylation as epigenetic mechanisms that could block the expression of tumor suppressor genes. It can be a potential therapeutic for cancer, neurodegenerative disorder and heart disease.

 

Figure: Acetylation and deacetylation of lysine residues.

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3380189_12263_2012_283_Fig1_HTML.jpg

References

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405764/

 

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25482/full

Third Article

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101110/pdf/cmr-3-117.pdf

 According to Martinet and Phillipe,  histones are proteins that wrap up the nuclear DNA and constitute a superstructure named chromatine which builds dynamic units called nucleosomes. The four core histones: H2A, H2B, H3 and H4, form an octameric histone surrender with 147 base pairs of DNA, and linked by histone H1.  The chromatine architecture is modified by histone acetyltransferases (HATs): Acetylation and deacetylation of specific lysine residue of histone.  This process can express or repress genes.

The comformation modification by histones produce “histone code”.  For instance. K9 in H3 converts chromatine into inactive form when methylated, phosphorylation of serine 10 is the same H3 that is needed for methylation of K4 and acetylation of K9 and K14. 

This research paper has shown that histone deacetylase inhibitor as a possible way to treat the human life threating diseases.  For instance, In October 2006 the FDA approved vorinostat (HDACi drug) for the treatment of advanced forms of cutaneous T-cell lymphoma.  But there are still some research requirements to approve bioactivity in vitro and in vivo of HDACi. 

 

 

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