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Apoptosis is one of several types of programmed cell death (PCD) and is characterized by a series of morphological changes, including nuclear condensation and fragmentation, and plasma membrane blebbing, which result in the formation of apoptotic bodies. Apoptosis is accompanied by several characteristic biochemical changes, including mitochondrial outer membrane permeabilization (MOMP), activation of the effector caspases caspase 3, caspase 6 and caspase 7, as well as the activation of catabolic hydrolases that degrade most of the macromolecules of the cell, which includes DNA. These morphological and biochemical hallmarks facilitate the detection of apoptosis, although cells that die in vivo are usually engulfed and degraded by healthy cells before they get the full apoptotic phenotype, which means that the incidence of apoptosis is usually underestimated.
Understanding the mechanisms of apoptosis is important and helps in the understanding of the pathogenesis of conditions as a result of disordered apoptosis. In turn, this may help in the development of drugs that target certain apoptotic genes or pathways. Caspases are central to the mechanism of apoptosis because they are both the initiators and executioners. There are three pathways by which caspases can be activated. The two commonly described initiation pathways are the intrinsic (mitochondrial) and extrinsic (death receptor) pathways of apoptosis. The intrinsic apoptotic pathway is initiated by various intracellular stimuli, including DNA damage, oxidative stress, hypoxia, and growth-factor deprivation, which induce outer mitochondrial membrane permeabilization. The extrinsic apoptotic pathway is activated by death receptors (DR), which are cell-surface receptors that bind specific ligands and transmit apoptotic signals. Such ligands include soluble molecules of the tumor necrosis factor (TNF) family, which are secreted as homotrimers and bind to members of the TNFR family, including Fas/CD95, TNFR-1, and TRAIL receptors DR-4 and DR-5. Both pathways eventually result in a common pathway or the execution phase of apoptosis. A third less well-known initiation pathway is the intrinsic endoplasmic reticulum pathway.
Cancer can be viewed as the result of a succession of genetic changes during which a normal cell is transformed into a malignant one, while evasion of cell death is one of the essential changes in a cell that cause this malignant transformation. In the 1970s, Kerr et al had linked apoptosis to the elimination of potentially malignant cells, hyperplasia and tumor progression. Therefore, reduced apoptosis or its resistance plays a crucial role in carcinogenesis. There are a number of ways a malignant cell can acquire reduction in apoptosis or apoptosis resistance. In general, the mechanisms by which evasion of apoptosis occurs can be broadly divided into: 1) disrupted the balance of pro-apoptotic and anti-apoptotic proteins, 2) reduced caspase function and 3) impaired DR signaling (Figure 1).
Figure 1. Mechanisms contributing to evasion of apoptosis and carcinogenesis.
Like a double-edged sword, every defect or abnormality along the apoptotic pathways could also be an interesting target of cancer treatment. Drugs or treatment strategies that can restore the apoptotic signalling pathways towards normality have the potential to eliminate cancer cells, which depend on these defects to stay alive. And many new treatment strategies targeting apoptosis are feasible and may be used in the treatment of various types of cancer.
Creative Biogene is able to offer a variety of apoptosis-related products including stable cell lines, viral particles and clones for your drug discovery projects.
Apoptosis Product Panel
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