Fighting Cancer with Powerful Proteasome Inhibition

04.04.2016
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When it comes to blood cancer Lymphoma is the most common. Lymphoma manifests in two general forms: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Uncontrollable proliferation of lymphocytes (category of white blood cells) leads to the development of cancerous lymphocytes which can ultimately metastasize to various parts of the body and cause tumors.

B-lymphocytes (B-cells) and T-lymphocytes (T-cells) are the immune system cell types commonly associated with lymphomas. Drugs which inhibit the normal function of the proteasome, which is to degrade protein products and prevent “degradation of the intracellular proteins, affecting signaling within cells,” ultimately results in two specific cellular paths: death of the cancer cell or “inhibition of growth” of the cancer cell (“Lymphomation”).  
 
The significance of HDAC (Histone Deacetylase) inhibition lies in its ability to keep DNA exposed for the binding of transcription factors to DNA sequences in the nucleus, via the “acetylaton of lysine residues” (“Lymphomatics”) thus preventing rewrapping of DNA into its highly coiled and packed state around proteins called histones via HDACs. Cancer’s ability to rapidly proliferate, heavily depends upon its ability to gain regulatory control over transcription factors such as those which promote cell growth, and to inhibit tumor suppressor protein functioning or bypass Cell Cycle DNA damage checkpoints.
 
The mechanism of action for certain drugs promoting HDAC inhibition follows the aforementioned model, and specifically “causes [in vitro] the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells” (“Merck”). It is important to consider two apoptotic pathways: the Intrinsic and the Extrinsic pathways. A signal for DNA damage can trigger the Intrinsic pathway cascade, prompting the release of cytochrome c from the Mitochondria, causing cleavage of Pro-Caspace-3 further downstream and ultimately resulting in apoptosis of the cell. HDAC inhibitors often bind receptors which would normally be involved in the Extrinsic pathway. The process only differs from the Intrinsic pathway due to the binding of “pro-apoptotic ligands” to the cell surface receptor (“Lymphomation”). A promising method of cancer treatment also gaining popularity among certain researchers and clinicians is to approach cancer treatment with a combination of therapies.  
 
References:
http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300151
http://www.lymphomation.org/treatment-pipeline.htm
https://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf

Image copyright: Mfotophile/thinkstock

Article last time updated on 05.04.2016.

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Medicine, Oncology, Research
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