A mechanism that has been well-looked-after throughout evolution, programmed cell death, or apoptosis, is essential for both tissue homoeostasis and embryonic development.1. The natural physiological reaction to a variety of stressors, including irreversible DNA damage, is apoptosis. Many illnesses develop as a result of either suppressing planned cell death (autoimmune disorders, cancer, and neurodegenerative diseases) or hyperactivating it (neurodegenerative diseases, immunodeficiency, and ischaemia-reperfusion injury). The equilibrium between intended cell death and growth is upset in cancer, and genetically aberrant cells are able to survive due to malfunctions in apoptotic pathways. According to Sjöström and Bergh (2001), the majority of cytotoxic, hormonal, and radiation therapies ultimately destroy cancer cells by rupturing cells irreversibly and inducing apoptosis.
Cells cut off communication with nearby cells early in the process of apoptosis. During early apoptotic cell death, membranes and organelles, including mitochondria, are largely retained. Demonstrated in both embryonic epithelia and cultured Marin-Darby canine kidney cells developing in monolayers, dying cells send out signals that trigger surrounding cells’ actin- and myosin-dependent processes (Ziegler & Groscurth, 2004) . Many cell types and species share striking similarities in the morphological changes associated with apoptotic cell death, which affect both the cytoplasm and the nucleus (Häcker, 2000).
. However, the time taken depends on the cell type, the stimulus and the apoptotic pathway (Ziegler & Groscurth, 2004).Broadly, three main types of biochemical changes can be observed in apoptosis: 1) activation of caspases, 2) DNA and protein breakdown and 3) membrane changes and recognition by phagocytic cells(Kumar et al., 2014). Phosphatidylserine has been “reversed out” of the inner layers of the cell membrane and is expressed in the outer layers during the early stages of apoptosis.This allows early recognition of dead cells by macrophages, resulting in phagocytosis without the release of pro-inflammatory cellular components(Hengartner, 2001a).This is followed by a characteristic breakdown of DNA into large 50 to 300 kilobase pieces (Silke: Mammalian Mitochondrial IAP Binding Proteins – Google Scholar, n.d.) It is crucial to remember that while some morphological changes in apoptosis can be partially explained by biochemical changes, apoptosis cannot be defined by biochemical analyses of DNA fragmentation or caspase activation because it can happen without oligonucleosomal DNA fragmentation and can also be caspase-independent. The Nomenclature Committee on Cell Death (NCCD) has suggested that the classification of cell death modalities should rely solely on morphological criteria, even though numerous biochemical assays and experiments have been used to detect apoptosis. This is because there is no definitive equivalency between ultrastructural changes and biochemical cell death characteristics (Galluzzi et al., 2007). The stimulation of caspases can happen via three different pathways. The intrinsic (also known as mitochondrial) and extrinsic (also known as death receptor) ways of apoptosis are the two starting pathways that are regularly discussed. Eventually, both machanism lead to the execution phase of apoptosis or a joint pathway. The intrinsic endoplasmic reticulum pathway is a third, less well-known initiation pathway (O’Brien & Kirby, 2008).
As the name recommends, the extrinsic death receptor pathway twitches when death ligands attach to a death receptor. The type 1 TNF receptor (TNFR1) and a associated protein termed Fas (CD95), along with its ligands TNF and Fas ligand (FasL), are the supreme well-known death receptors, regardless of the point that some others have been identified (Hengartner, 2001b). The death-inducing signaling complex (DISC) is the term given to the compound of ligand, receptor, and adaptor protein that is shaped when the death ligand binds to the death receptor. O’Brien & Kirby (2008). DISC then initiates the assembly and activation of pro-caspase 8/10. The activated form of the enzyme, caspase 8/10 is an initiator caspase, which initiates apoptosis by cleaving other downstream or executioner caspases 3/6/7 (Karp, 2009) .
Intrinsic pathway is initiated within the cell. Internal stimuli such as irreparable genetic damage, hypoxia, extremely high concentrations of cytosolic Ca2+ and severe oxidative stress are some triggers of the initiation of the intrinsic mitochondrial pathway (Karp, 2009) Regardless of the stimuli, this pathway is the result of increased mitochondrial permeability and the release of pro-apoptotic molecules such as cytochrome-c into the cytoplasm . A family of proteins called Bcl-2, which became its name from the BCL2 gene that was first revealed at the chromosomal breakpoint of the translocation of chromosome 18 to 14 in follicular non-Hodgkin lymphoma, is accountable for tightly regulating this pathway (Wong, 2011). According to Reed (1997), there are two main categories of Bcl-2 proteins: pro-apoptotic proteins (like Bax, Bak, Bad, Bcl-Xs, Bid, Bik, Bim, and Hrk) and anti-apoptotic proteins (like Bcl-2, Bcl-XL, Bcl-W, Bfl-1, and Mcl-1). Pro-apoptotic proteins purpose by boosting the release of cytochrome c from mitochondria, while anti-apoptotic proteins control apoptosis by stopping this release. It is not the absolute quantity but rather the balance between the pro- and anti-apoptotic proteins that determines whether apoptosis would be initiated(Wong, 2011).Cytoplasmic release of cytochrome c activates caspase 3 via the formation of a complex known as apoptosome which is made up of cytochrome c, Apaf-1 and caspase 9(Kroemer et al., 2007). A several number of caspases are activated through the execution stage of apoptosis. Caspase 9 is the upstream caspase for the intrinsic pathway, while caspase 8 is the upstream caspase for the extrinsic pathway. To influence caspase 3, the intrinsic and extrinsic routes converge. Caspase 3 then cleaves the inhibitor of the caspase-activated deoxyribonuclease, which is responsible for nuclear apoptosis (Ghobrial et al., 2005) In addition, downstream caspases induce cleavage of protein kinases, cytoskeletal proteins involved in cell division, repair proteins and inhibitory protein of endonucleases family. They also have an effect on the cytoskeleton, cell cycle and signaling pathways, which together contribute to the typical morphological changes in apoptosis(Wong, 2011)
Targeting antiapoptotic proteins like Bcl-2 family of proteins by use of therapeutic agents (oblimersen) sodium, to inhibit the Bcl-2 family of anti-apoptotic proteins or the silencing of the upregulated anti-apoptotic proteins or genes involved.(Wong, 2011)The ability of tumor cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens. Research pains have been focused on the development of mechanisms by tumor cells to evade engagement in cell death and the intricacies of apoptosis.