Cancer is a fatal disease associated with uncontrolled growth of cells and not regulated in our body. This disease requires a large number of deaths worldwide. According to statistics provided by WHO (World Health Organization), the number of cancer deaths increased by 45%. This disease can affect almost any part of our body. Initially, it appears as a small lump or mass, but turns out to be deadly when it spreads throughout the body via the bloodstream or lymphatic system.
Agents that cause cancer are numerous, such as unhealthy lifestyles, exposure to carcinogenic pollutants or radiation, some viral infections, etc. These agents ultimately stimulate the genetic defects in our cells. Genetic abnormalities appear as 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 oncogenes hyperactivation.
Gene expression of proteins in eukaryotes is controlled at different stages in many ways. This control mechanism starts from the stage of chromatin. Histone acetyltransferase (HAT) and histone deacetylases (HDACs) are two sets of enzymes that show opposite effect on modifications of chromatin and thus regulate gene expression. Under the action of hats, the chromatin becomes more relaxed to increase the accessibility of transcription factors to DNA. This stimulates gene transcription while HDACs are more condensed chromatin and repress the transcription process. An increase in HDAC activity or inactivity of hats, was noticed in many tumors. It is difficult to induce an enzyme under physiological conditions by pharmacological agents. Therefore induce the activity of HATS is quite difficult when compared to the inhibition of HDAC activity pharmacologically. This makes it a potential target HDAC in clinical studies. HDACs have the potential to alter the epigenetic status of a cell. Apart from histones, HDACs also target certain non-histone proteins, such as transcription factors, heat shock proteins, etc. Therefore, they can also modulate various cellular processes [1].
Histone deacetylases are a group of enzymes that are classified into four different groups. Among them, HDACs from classes I, II and IV are also known as classical HDACs whereas HDACs belonging to class III are known as sirtuins [2]. The compounds that 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 on their chemical structure and its power to inhibit a particular enzyme HDAC. Almost all HDACi have a common pharmacophore. This pharmacophore unit consists of a zinc binding group that assists in the chelation of the cation in the HDAC catalytic domain. Apart from this cap also contains a pharmacophore, connecting unit and a linker.
HDACi show multiple biological activities in a cancer cell as:
Stimulation of apoptosis
HDACi have an inherent ability to induce apoptosis in tumor cells. An additional advantage of these inhibitors is that they selectively stimulate the apoptotic process in tumor cells and leave normal cells unaffected. Some side effects like nausea, fatigue and thrombocytopenia were observed, but can be managed clinically. HDACi show different actions depending on cell type. In addition HDAC inhibitors that vary in different structures show different effects in the same cell type. SAHA or Vorinostat example shows a widespread activity in comparison Tubacin [3].
LIGAND STIMULATION OF DEATH (death pathway EXTRINSIC)
In vitro studies using tumor cell lines have shown that apoptosis induced by HDACi is largely due to stimulation of the death receptor pathway. In vivo studies were performed in the case of transgenic mice that developed AML. During the administration of Valaporate, death ligands such as FAS and TRAIL were induced, therefore, to stimulate the process of apoptosis. However clinical trials in this line are to be done [3].
STIMULATION OF THE WAY OF DEATH MITOCHONDRIAL or intrinsic
HDAC inhibitors to regulate gene expression pro-and anti-apoptotic. It stimulates the expression of proapoptotic proteins that in turn activate apoptosis through the intrinsic death. In vitro studies have proven this fact, but in vivo studies are still needed [3].
REGULATION OF ACTIVITY ROS
HDAC inhibitors increase levels of reactive oxygen species followed by changes in mitochondrial membrane potential. Various anti-free radicals have the potential to reverse this effect. However, the exact mechanism by which free radicals are increased is not well understood. Free radicals can be produced by either active process that is further enhanced by the increased production of ROS or due to changes in the expression of ROS-regulatory proteins (thioredoxin and Tbp2) [3]. Further studies are still needed in this line.
Cell cycle arrest
HDAC inhibitors promote cell differentiation by arresting the cell cycle phase Gap1. This cell cycle arrest is known to be mediated by the retinoblastoma protein. In fact, all except Tubacin HDAC inhibitors have the potential to arrest the cell cycle. The mechanism underlying the G1 arrest was considered 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 [3].
Anti-angiogenic and anti-invasive HDACi
The results of in vitro and in vivo show that HDAC inhibitors can control the process of angiogenesis (powering down nutrients) and metastasis of tumor cells. It checks the development of the tumor and prevent it from spreading. The mechanism behind this action is the expression of genes induced by HDACi proangiogenic. The process of metastasis is controlled by HDACi induced by the removal of matrix metalloproteases [3].
Modulate the immune system
HDAC inhibitors modify the malignant cells so that they become potent immune targets. They can also alter cytokine production. The reason behind the enhanced immunogenicity of tumor cells induced HDACi was associated with increased expression of MHC class I and II proteins and increased expression of costimulatory molecules such as CD86, CD80, ICAM1, and CD40 [3].
Initially it was understood that HDACi can regulate gene expression by histone acetylation. But now its is well known that HDACi can stimulate a greater diversity of biological effects by affecting various molecular processes such as 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 was tested in combination with conventional chemotherapeutic agents, modulators of transcription, ligands of death receptors, regulators of proteasome degradation and kinase inhibitors. A significant successes achieved during clinical studies makes oncologists equipped with a new weapon against this deadly disease, cancer.
