Saturday, 9 February 2013

A new selective inhibitor of Histone Deacetylase 6

Chemotherapy, treatment of cancer with drugs, requires the development of compounds which have the effect of slowing tumour growth, stopping growth all together or even causing death to cancer cells within the tumour. Generally, compounds can either act to positively stimulate a response within cells or to inhibit one or more processes. These compounds will normally be designed to target a single protein or multiple proteins in the same family. There are advantages and disadvantages to targeting more than one protein: on the plus side you may help kill cancer cells by stopping several proteins in the same signalling pathway or prevent more than one pathway, on the downside you can increase the chance that the compound will also target non-cancerous cells and increase side effects for patients. One way to lessen this effect is to try and specifically target the compound to only the tumour thus limiting its effects on surrounding healthy cells, an alternative is to make the compound more specific for its intended target and reduce off-target effects. Compounds that not only show these properties, but also enter the body easily, are absorbed at a desirable rate and are successfully cleared from the body without creating dangerous metabolites, are likely to make suitable drugs. Here is where the fields of drug design, pharmacology and cancer research combine in an attempt make more effective therapeutic agents for the treatment of cancer.

Drug development can take several approaches, firstly there are a number of compounds that exist in nature such as the anti-cancer drug Taxol which was found in the Pacific Yew tree Taxus brevifolia in the late 1960s. Often, but not always, chemists can find ways to make these natural products from reactions between other chemicals, increasing the amount of drug that can be produced from these sometimes rare natural products. Additionally, once the chemical structure of these natural products is known, medicinal chemists can make small changes to a compound's structure and look to see what effect this has on the anti-cancer activity of the resulting compounds, this is called structure activity relationship (SAR). These methods are the usual route of drug discovery by academic groups, however in the pharmaceutical industry vast libraries of compounds which have drug-like properties are screened for interactions with desired target proteins, or their ability to stop cancer cell growth. This effort is called high throughput screening (HTS), it is expensive but often finds compounds which can undergo SAR to finally produce potential drugs.

Kaliszcak and colleagues recently developed an anti-cancer drug based on two natural inhibitors of a class of proteins called histone deacetylases (HDACs). I mentioned in a previous post that DNA is tightly held together in a structure called chromatin, to build chromatin DNA is wound around proteins called histones. These histones can be modified by adding acetyl groups which loosens the chromatin structure making DNA more accessible, HDACs can remove these acetyl groups causing DNA to become more tightly wound and inaccessible. HDACs also target proteins other than histones for deacetylation such as alpha-tubulin, a protein involved in the cell cycle that can be acetylated. The HDAC6 inhibitor prevented the deacetylation of alpha-tubulin by HDAC6 and caused an increase in the levels of the acetylated form. This effect on alpha-tubulin makes inhibiting HDACs, including HDAC6, a potential treatment for cancer. However, many current HDAC inhibitors are very unspecific and have serious side effects. The inhibitor developed by Kaloszcak and colleagues targets HDAC6 but at much lower concentrations of drug than required to target other HDACs such as HDAC1, suggesting it is more selective for HDAC6. This inhibitor had potent anti-cancer effects, causing a reduction in the growth of a wide variety of cancer cell types including: breast, colon, lung, ovarian and prostate cancer. 

The group also showed that their HDAC6 inhibitor caused cancer cells to undergo cell death. They did this by measuring the DNA content of cells after treatment with their HDAC6 inhibitor; DNA content decreased, a sign that cells are undergoing cell death. They noticed that proteins called caspases, important in a specific type of controlled cell death called apoptosis, were increased. Finally, when used in a mouse model of cancer, these inhibitors worked to reduce tumour growth with no general toxicity suggesting this HDAC6 inhibitor may do well if transferred into human clinical trials. 

Mentioned Articles

Kaliszczak M, Trousil S, Aberg O, Perumal M, Nguyen QD, Aboagye EO. (2013)
Br J Cancer. 2013 Feb 5;108(2):342-50. doi: 10.1038/bjc.2012.576. Epub 2013 Jan 15. (2009) Paclitaxel (Taxol) : Cancer Research UK : CancerHelp UK. [online] Available at: [Accessed: 9 Feb 2013].

Aldana-Masangkay GI, Sakamoto KM.(2011)
J Biomed Biotechnol. 2011;2011:875824. doi: 10.1155/2011/875824. Epub 2010 Nov 7.

Gryder BE, Sodji QH, Oyelere AK (2012)
Future Med Chem. 2012 Mar;4(4):505-24. doi: 10.4155/fmc.12.3.

Annunziato, A. (2008) 
Nature Education 1(1)

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