The process of apoptosis is a cascade involving several reactions and processes that are controlled by enzymes. In these processes destruction of proteins and other contents of the cell are brought about. There are mainly two apoptotic pathways namely the extrinsic and the intrinsic pathway. The extrinsic pathway initiates from the external of the cell and certain pro-apoptotic receptors present on the cell wall are activated by the pro-apoptotic ligands (namely Apo2L/TRAIL which binds to DR4 & DR5, and CD95L/FasL which binds to CD95 and Fas.
The extrinsic pathway does not depend on the p53 protein). The intrinsic pathway occurs from within the cell and is a reaction to damage of DNA, abnormal cell cycle, hypoxia, etc. The pro-apoptotic enzymes present activate the mitochondria to release caspases that ultimately result in apoptosis and destruction of the cell. Inside the cell, the caspases plays a vital role in induction, transduction, amplification and execution of various apoptotic processes.
The caspases contain a group of enzymes that are activated by the intrinsic or the extrinsic pathways. Initiator caspases include caspases 2, 8, 9 and 10, and execution caspases include caspases 3, 6 and 7. The initiator caspases through complex reactions activate the effecter caspases (Research Apoptosis, 2009). HDAC (Histone deacetylase) inhibitions are substances that result in reduce proliferation and permits differentiation of cells and cause apoptosis of the cancerous cells (when studied in the laboratory).
In the body, they cause the acetylated nuclear histones (by acteylation of histones) to rise in the normal and the tumour cells, by catalysing the elimination of acetyl modification on the lysine-originating proteins (through inhibition of the histone deactylase enzyme) (Secrist 2003). In this way it acts as a surrogate marker to determine the HDAC inhibitor activity. The HDAC activity (along with histone acetyltransferases or HATs) also stimulates transcription of certain genes such as cyclin-dependent kinase inhibitor p21WAF1/CIP1, whereas it tends to obstruct the activity of other genes.
Several transcription factors especially GATA-1, p53 and oestrogen receptor-alpha tend to get acetylated. The exact mechanism by which the tumour cells are prevented from growing, differentiating and undergoing apoptosis needs to be studied further. However, it has been found that when the HDAC and HATs levels lowers gene expression may be altered, which is observed in several cancers. Several silenced tumour suppressor cells tend to get activated that cause decreased differentiation and increased apoptosis of the cells. The cells become more sensitive to the action of substances that stimulate apoptosis on the cell surface (such as TRAIL).
HDAC specifically enhance the effect of death receptor agonists on leukemic cells. HDAC inhibitors are known to cause apoptosis of the cancer cells in the laboratory and hence are of immense use in human biomedical studies. The drugs are potentially safe and effective to use and is promising to treat several forms of cancers (Vigushin 2002). During the process of carcinogenesis, the normal cells of the body are converted into cancerous cells, and tumour suppressor genes get inactivated (by mutations, deletions, silencing, etc).
The chromatin undergoes structural changes leading to silencing of the tumour suppressor genes. The DNA undergoes methylation and histone deacetylation changes. Drugs that actually encourage inhibition of DNA methylation are promising in the field of cancer therapy. HDAC can regulate the deacetylation of the histones and can prevent the cancerous cells from multiplying by reactivating the tumour suppressor genes. The epigenetic mechanism can be stimulated by which the suppressor genes for tumours are reactivated (Polinsky 2007).