Tuesday, March 13, 2012
ROLE OF HDAC INHIBITORS IN THE FIGHT AGAINST CANCER
The deadly disease cancer is associated with an uncontrolled and unregulated growth of cells within our body. This disease is claiming a large number of deaths across the world. According to the statistics provided by WHO (World Health Organization), the number of deaths due to cancer have increased by 45%. This disease can affect almost any part within our body. Initially it appears as a small lump or mass but proves to be deadly when it spreads all over the body through blood or lymphatic system.
Causative agents for cancer are many, like unhealthy lifestyle habits, exposure to carcinogenic pollutants or radiations, few viral infections etc. These causative agents ultimately stimulate genetic defects within our cells. The genetic defects appear in the form of chromosomal aberrations or gene mutations (deletion or insertion of genes). The ultimate effect of these genetic effects is the suppression of tumor suppressor genes or hyperactivation of oncogenes.
The expression of genes into proteins within eukaryotes is controlled at different stages in a large number of ways. This control mechanism starts right from the chromatin stage. Histone acetyltransferases (HAT) and histone deacetylases (HDAC) are two sets of enzymes which show opposing effect on the chromatin modifications and hence regulate the expression of genes. Under the action of HATs, the chromatin gets more relaxed increasing the accessibility of transcription factors to DNA. This stimulates the transcription of genes whereas HDACs make the chromatin more condensed and repress the process of transcription. An increased activity of HDACs or inactivity of HATs, has been noticed in large number of tumors. It is difficult to induce an enzyme under physiological conditions through pharmacological agents. Hence inducing the activity of HATs is rather difficult in comparison to inhibition of the activity of HDACs pharmacologically. This makes HDACs a potential target in clinical studies. HDACs have a potential to alter the epigenetic status of a cell. Apart from histones, HDACs also target certain non-histone proteins like transcription factors, heat-shock proteins etc. As a result they can modulate various cellular processes also .
Histone deacetylases are a group of enzymes which are classified into 4 different groups. Amongst them the HDACs belonging to classes I, II and IV are also known as classical HDACs whereas the HDACs which belong to class III are known as sirtuins . The compounds which target these enzymes and inhibit their action are known as HDAC inhibitors (HDACi). These inhibitors are either obtained after extraction from natural sources or are chemically synthesized. The classification of HDAC inhibitors is based upon their chemical structure and its potency to inhibit a particular HDAC enzyme. Almost all the HDACi possess a common pharmacophore. This pharmacophore unit consists of a zinc binding group which helps in the chelation of the cation to the catalytic domain of HDAC. Apart from this a pharmacophore also contains cap, connecting unit and a linker.
HDACi show multiple biological activities within a cancerous cell like:
STIMULATION OF APOPTOSIS
HDACi have an inherent capacity to induce apoptosis within the tumor cells. An added benefit of these inhibitors is that they selectively stimulate this apoptotic process within the tumor cells and leave the normal cells unaffected. Some side effects like nausea, fatigue and thrombocytopaenia have been noticed but can be clinically managed. HDACi show different actions depending on the cell type. On the other hand different HDAC inhibitors which vary in their structures show different effects within the same cell type. For example SAHA or Vorinostat shows a widespread activity in comparison to Tubacin .
STIMULATION OF DEATH LIGANDS (EXTRINSIC DEATH PATHWAY)
In vitro studies using human tumor cell lines have shown that HDACi induced apoptosis is largely through stimulation of the death receptor pathway. In vivo studies were performed in case of transgenic mice which developed AML. Upon administration of Valaporate, death ligands like FAS and TRAIL were induced, hence stimulating the process of apoptosis. However clinical trials in this line are yet to be done .
STIMULATION OF MITOCHONDRIAL OR INTRINSIC DEATH PATHWAY
HDAC inhibitors regulate the expression of pro and anti-apoptotic genes. It stimulates the expression of pro-apoptotic proteins which in turn activate the apoptosis through the intrinsic death pathway. In vitro studies have proved this fact but in vivo studies are yet to be done .
REGULATION OF ROS ACTIVITY
HDAC inhibitors elevate the levels of reactive oxygen species followed by the changes in the mitochondrial membrane potential. Various free-radical scavengers have the potential to reverse this effect. However the exact mechanism by which the free radicals are increased is still not well understood. Free radicals can either be produced by active process which gets further enhanced by the increased ROS production or due to alterations in the expression of ROS-regulatory proteins (thioredoxin and TBP2) . Further studies are yet to be done in this line.
ARRESTING CELL CYCLE
HDAC inhibitors promote the cellular differentiation by arresting the cell cycle at the Gap1 phase. This arrest of the cell cycle is known to be mediated by the retinoblastoma proteins. In fact all the HDAC inhibitors except Tubacin have the potential to arrest the cell cycle. The underlying mechanism behind G1 arrest has been found to be the transcriptional activation of CDKN1A. HDAC inhibitors also activate the G2 phase check point. However the mechanism behind the HDACi stimulated G2 arrest is not well defined .
ANTI-ANGIOGENIC AND ANTI-INVASIVE PROPERTIES OF HDACi
Results from in vitro and in vivo studies show that HDAC inhibitors can control the process of angiogenesis (cut the supply of nutrients) and metastasis within tumor cells. This checks the tumor development and prevents it from getting spread. The mechanism behind this action is HDACi induced expression of pro-angiogenic genes. The process of metastasis is controlled by HDACi induced suppression of matrix metalloproteinases .
MODULATE THE IMMUNE SYSTEM
HDAC inhibitors modify the malignant cells in such a way that they become potent immune targets. They can also alter the cytokine production. The reason behind the increased immunogenicity of HDACi induced tumor cells has been related to the increased expression of MHC class I and II proteins along with the increased expression of co-stimulatory molecules like CD86, CD80, ICAM1, and CD40 .
Initially it was understood that HDACi can regulate the gene expression through histone acetylation. However now its is well known that HDACi can stimulate more diverse biological effects by affecting various molecular processes like DNA replication, mitosis, DNA repair etc. They have shown promising results when administered alone. However their combination with other agents proved to be more successful. It has been tested in combination with conventional chemotherapeutic agents, transcriptional modulators, death receptor ligands, proteasomal degradation regulators and kinase inhibitors. A significant success achieved during clinical studies makes the oncologists equipped with a new weapon to fight against the deadly disease, cancer.
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2. Dickinson M, et al. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs, 2010 Dec, 28 Suppl 1, S3-20.
3. Bolden JE, et al. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov, 2006 Sep, 5(9), 769-84.