Elizabeth A. Dunlap/Sandbox 1: Difference between revisions

Vorinostat (Zolinza) is an oral drug used as a cancer therapy to treat cutaneous T-cell lymphoma (CTCL) <ref name="one">Duvic, M., & Vu, J. (2007). Update on the treatment of cutaneous T-cell lymphoma (CTCL): Focus on vorinostat. Biologics : Targets & Therapy, 1(4), 377–392. doi:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721288/</ref>. Vorinostat, previously known as suberoylanilide hydroxamic acid (SAHA), was the first HDAC inhibitor to be approved by the U.S. Food and Drug Administration on October 6, 2006 <ref name="two">National Cancer Institute. (2013). FDA Approval for Vorinostat. doi:https://www.cancer.gov/about-cancer/treatment/drugs/fda-vorinostat</ref>. Cancer cells tend to over-express histone deacetylase (HDAC). HDAC removes acetyl groups on histones which results in a structural change of chromatin. This change in chromatin structure leads to the repression of gene expression which would result in the proliferation of cancer cells. Vorinostat is an HDAC inhibitor that ultimately stops the uncontrolled growth of the cancer cells. Vorinostat does this by inhibiting the function of HDAC by binding to its zinc-binding site and blocking the removal of acetyl groups. Vorinostat is taken once a day by mouth. The most common side effects were fatigue and gastrointestinal symptoms. <ref name="one"/>  

Zolinza contains vorinostat which is a histone deacetylase (HDAC) inhibitor. It’s IUPAC name is N'-hydroxy-N-phenyloctanediamide<ref name="three">Grant, S., Easley, C., & Kirkpatrick, P. (2007) Fresh from the Pipline, Vorinostat. Nature Publishing Group. doi:http://www.nature.com/nrd/journal/v6/n1/full/nrd2227.html</ref>. Vorinostat has a molecular formula of C₁₄H₂₀N₂O₃ and a molecular weight of 263.32 g/mol<ref name="four">Bubna, A. (2015) Vorinostat - An overview. Indian J Dermatol. 60:419.

doi:http://www.e-ijd.org/article.asp?issn=0019-5154;year=2015;volume=60;issue=4;spage=419;epage=419;aulast=Bubna</ref>.  It has a melting point ranging from 159 to 160.5 degrees Celsius. This HDAC inhibitor is completely soluble in dimethylsulfide, somewhat soluble in water, ethanol, isopropanol, and acetone, and insoluble in methylene chloride<ref name="five">Merck & Co Inc. (2015). Highlights of Prescribing Information: Zolinza. doi:https://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf</ref>. It’s pH value in water solution is 6.6 with a pKa value of 9.2 <ref name="four"/>.  All HDAC inhibitors consist of three different domains: a cap group that interacts with the binding pocket, a zinc binding domain (ZBD) that matches to the active site of the zinc ion, and a linker which binds the two together<ref name="six">Mottamal, M., Zheng, S., Huang, T. L., & Wang, G. (2015). Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents. Molecules, Vol 20, Iss 3, Pp 3898-3941. doi:www.mdpi.com/1420-3049/20/3/3898/pdf</ref>.

 

Zolinza is a potent nanomolar inhibitor of histone deacetylase (HDAC) activity, and this inhibition of activity can alternate the transcription of numerous genes via acetylation and transcription factors. It induces growth arrest, differentiation, or apoptosis in a variety of transformed cells, and its primary mechanism is to correct any abnormal balance between acetylated and deacetylated histones<ref name="seven">Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 1998; 12:599–606.</ref>. Zolinza inhibits HDAC activity by binding to the pocket of the catalytic site of the HDAC enzyme, and its hydroxamic acid moiety, an important moiety in the field of cancer therapy and a mutagenic agent, binds to a zinc atom of the enzyme with the rest of the molecule lying along the surface of the HDLP (histone deacetylase-like protein). Zolinza induces up to a nine-fold increase in p21WAF1 (a cell kinase inhibitor) mRNA and protein in T24 bladder carcinoma cells. This is caused by an increase in the rate of gene transcription associated with acetylation of the histones H3 and H4, associated with the p21WAF1 promoter. Zolinza also promotes the acetylation of numerous transcription factors like the androgen receptor, E2F-1, YY1, Smad7, EKLF, etc. In addition to histones and transcription factors, it also shows the acetylation of lysine residues of proteins, such as a-tubulin and protein Hsp90. Inhibition of HDAC6 activity leads to acetylation and the disruption of Hsp90, which leads to the decreased of progrowth activity and survival of proteins such as Bcr-Abl, mutant FLT-3, c-Raf and AKT in human leukaemia cells. Zolinza has the ability to influence the ability of tumor cells to undergo mitosis by disrupting the cell cycle and induce apoptosis of tumor cells by targeting cell cycle checkpoints. In vitro studies show that HDAC inhibitors create spindles that interfere with chromosome attachment, resulting in mitotic accumulation without affecting microtubules<ref name="four"/>.