Tuesday, March 20, 2012



The inhibitors of histone deacetylases control the levels of HDAC enzymes and hence stimulate a large variety of intra- and extracellular functions. Some inhibitors selectively control few functions like- transcription factor’s regulation, remodeling of chromatin, acetylation of histone and non-histone proteins. Choice of an appropriate inhibitor to control cancer also becomes essential. A widespread research was involved in the synthesis of Droxinostat.


The inhibitors to HDACs finally stimulate the process of differentiation or apoptosis within the cancerous cells. These inhibitors alter the transcription of those genes which are involved in the extrinsic and intrinsic pathways of apoptosis. Some even stimulate the aggresome or proteasome mediated apoptosis. They stimulate the hyperacetylation of the histone proteins and hence stimulate diverse effects within the cells. The HDAC enzymes are broadly classified into four different groups. The transcriptional activators or HDACs stimulate the transcription of many genes. The inhibitors to these HDACs are classified based on their structures. Each inhibitor is so designed that it can inhibit specific HDAC enzyme or a set of HDACs belonging to one class. Structurally they have a unique pharmacophore unit which contains a cap. This unit is attached to a linker, connecting unit and a group which is capable of binding to the zinc 2+ ion. This group allows the cation to bind with the catalytic domain of the HDAC enzyme. The HDACs belonging to class I, II and IV are commonly controlled by the inhibitors trichostatin A, vorinostat and panobinostat. These inhibitors are also known as broad spectrum inhibitors as they can control many HDACs at the same time [1]. Droxinostat sensitizes the cells to the death receptor stimuli.


Some inhibitors like romidepsin, entinostat, valproate are highly specific in their action as they inhibit the action of only those HDACs which belong to class I [1]. Droxinostat also shows very specific action. During the process of its synthesis Ethyl 4-bromobutyrate was initially used and subjected to various processes to obtain a suspension of Droxinostat. This inhibitor was used to study the gene expression profile. It was tested for its - action against HDACs, cell viability and molecular docking properties [3].


Some cells which are resistant to the death stimuli are sensitized by certain molecules like droxinostat. As a result cells start receiving the death stimuli in the form of decreased expression of FLIP which is an inhibitor of caspase 8. The downregulation of FLIP sensitizes the cells to TRAIL ligand and related TRAIL mediated apoptosis [2]. The changes in the gene expression were similar to those noticed after the treatment with other inhibitors of HDACs. Further analysis helped in concluding that Droxinostat inhibits HDAC6, HDAC8 and HDAC3. This inhibition of HDACs sensitized the cells to death ligands [3]. Some other molecules like fasentin are also considered to be sensitizers to the receptors of death stimuli. Fasentin is a sensitizer to FAS and TNF mediating apoptosis stimulating ligand. This inhibitor targets the expression of genes which are involved in the uptake of nutrients. When these genes are suppressed the cells are deprived of glucose as a result of which they die [4].


In summary, Droxinostat is a novel discovery which makes a cancerous cell sensitive to various death signals. Hence the ultimate effect of this inhibitor is apoptosis.


1. Dickinson M, Johnstone RW, Prince HM. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs 2010 Dec; 28 Suppl 1:S3-20.
2. Kauh J, Fan S, et al. c-FLIP Degradation Mediates Sensitization of Pancreatic Cancer Cells to TRAIL-Induced Apoptosis by the Histone Deacetylase Inhibitor LBH589. PLoS One 2010; 5(4): e10376.
3. Wood TE, Dalili S, et al. Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands. Mol Cancer Ther 2010 Jan; 9(1):246-56.
4. Wood TE, Dalili S, et al. A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death. Mol Cancer Ther 2008 Nov; 7(11):3546-55.

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