They could be mutants that would become cancerous--apoptosis is therefore very important in the formation or nonformation of cancer. Also, positive and negative selection occur among the cells of the immune system.
Cells that recognize 'self' that is, ones that would attack the organism's own cells are instructed to die during this process. Finally, cells that are infected by a virus can sometimes recognize the infection and kill themselves before the virus has time to replicate and spread to other cells.
Cell death is common among plants, especially among the higher plants. The xylem in trees, through which water rises to the leaves, consists of spaces left by dead cells. Cell death occurs very visibly when deciduous trees drop their leaves in the fall. Incidentally, this is where the name 'apoptosis' comes from: it is the Greek word for the falling of leaves from trees, as well as the losing of hair from balding men--which incidentally is also thought to involve apoptosis!
Plant cells cannot move, so plants use a slash-and-burn technique to cope with infection: all the cells in an infected area may kill themselves to halt the spread of the disease. The answer gets caught up in a question of semantics between a cell choosing to die and being forced to die. But some forms of programmed death are found in unicellular organisms, including bacteria.
The death of the mother cell during sporulation, the process in which spores are created, could be considered a kind of programmed cell death. Certain parasites, such as trypanosomes which cause malaria , change form to elude the immune response from their host; the laggards who o fail to undergo the change will die off in a kind of cellular altruism.
And a leaf falls off a tree when it's dead. And apoptosis refers to a process of what's called programmed cell death where the cell is actually in a funny kind of way committing suicide. And when this happens, there's a whole scripted choreography of pathways and proteins within a cell that get activated to actually kill the cell and without making too much of a mess. And this happens normally during development, for instance, in the development of the hand, that normally to begin with, the hand looks very much like a duck paddle foot and the webs between the fingers.
Those cells apoptose, giving you the fingers. Although a few studies managed to go as far as phase III clinical trials, no final approval from the FDA has been granted so far [ 75 ]. Another interesting p53 gene-based strategy was the use of engineered viruses to eliminate pdeficient cells.
One such example is the use of a genetically engineered oncolytic adenovirus, ONYX, in which the E1B kDa gene has been deleted, giving the virus the ability to selectively replicate in and lyse tumour cells deficient in p53 [ 76 ]. Several drugs have been investigated to target p53 via different mechanisms. One class of drugs are small molecules that can restore mutated p53 back to their wild-type functions.
For example, Phikan, a small molecule and carbazole derivative, has been shown to bind to and restore mutant p53 [ 77 ]. Another small molecule, CP, has been found to intercalate with DNA and alter and destabilise the DNA-p53 core domain complex, resulting in the restoration of unstable p53 mutants [ 78 ]. Other drugs that have been used to target p53 include the nutlins, MI and the tenovins. Nutlins are analogues of cis-imidazoline, which inhibit the MSM2-p53 interaction, stabilise p53 and selectively induce senescence in cancer cells [ 79 ] while MI was reported to disrupt the MDM2-p53 interaction, resulting in inhibition of cell proliferation, selective apoptosis in tumour cells and complete tumour growth inhibition [ 80 ].
The tenovins, on the other hand, are small molecule p53 activators, which have been shown to decrease tumour growth in vivo [ 81 ]. Several clinical trials have been carried out using p53 vaccines. In a clinical trial by Kuball et al , six patients with advanced-stage cancer were given vaccine containing a recombinant replication-defective adenoviral vector with human wild-type p When followed up at 3 months post immunisation, four out of the six patients had stable disease.
However, only one patient had stable disease from 7 months onwards [ 82 ]. Other than viral-based vaccines, dendritic-cell based vaccines have also been attempted in clinical trials. Svane et al tested the use of p53 peptide pulsed dendritic cells in a phase I clinical trial and reported a clinical response in two out of six patients and pspecific T cell responses in three out of six patients [ 83 ].
Other vaccines that have been used including short peptide-based and long peptide-based vaccines reviewed by Vermeij R et al. When designing novel drugs for cancers, the IAPs are attractive molecular targets. It effectively inhibits the intrinsic as well as extrinsic pathways of apoptosis and it does so by binding and inhibiting upstream caspase-9 and the downstream caspases-3 and -7 [ 85 ].
Using the antisense approach, inhibition of XIAP has been reported to result in an improved in vivo tumour control by radiotherapy [ 86 ]. When used together with anticancer drugs XIAP antisense oligonucleotides have been demonstrated to exhibit enhanced chemotherapeutic activity in lung cancer cells in vitro and in vivo [ 87 ].
Many studies have investigated various approaches targeting Survivin for cancer intervention. One example is the use of antisense oligonucleotides. Grossman et al was among the first to demonstrate the use of the antisense approach in human melanoma cells. The anti-sense approach has also been applied in head and neck squamous cell carcinoma and reported to induce apoptosis and sensitise these cells to chemotherapy [ 91 ] and in medullary thyroid carcinoma cells, and was found to inhibit growth and proliferation of these cells [ 92 ].
Besides, small molecules antagonists of Survivin such as cyclin-dependent kinase inhibitors and Hsp90 inhibitors and gene therapy have also been attempted in targeting Survivin in cancer therapy reviewed by Pennati et al.
Several drugs have been designed to synthetically activate caspases. For example, Apoptin is a caspase-inducing agent which was initially derived from chicken anaemia virus and had the ability to selectively induce apoptosis in malignant but not normal cells [ ]. Another class of drugs which are activators of caspases are the small molecules caspase activators. These are peptides which contain the arginin-glycine-aspartate motif. They are pro-apoptotic and have the ability to induce auto-activation of procaspase 3 directly.
They have also been shown to lower the activation threshold of caspase or activate caspase, contributing to an increase in drug sensitivity of cancer cells [ ]. In addition to caspase-based drug therapy, caspase-based gene therapy has been attempted in several studies. For instance, human caspase-3 gene therapy was used in addition to etoposide treatment in an AH liver tumour model and was found to induce extensive apoptosis and reduce tumour volume [ ] while gene transfer of constitutively active caspse-3 into HuH7 human hepatoma cells selectively induced apoptosis in these cells [ ].
Also, a recombinant adenovirus carrying immunocaspase 3 has been shown to exert anti-cancer effects in hepatocellular carcinoma in vitro and in vivo [ ]. Recently, many new molecules that target apoptosis enter various stages of clinical trials. These molecules target various proteins involved in apoptosis. Many are antagonists of IAPs and molecules that target the Bcl-2 family of proteins. Table 3 summarises ongoing or recently completed clinical trials involving molecules that target apoptosis.
The abundance of literature suggests that defects along apoptotic pathways play a crucial role in carcinogenesis and that many new treatment strategies targeting apoptosis are feasible and may be used in the treatment of various types of cancer. Some of these discoveries are preclinical while others have already entered clinical trials. Many of these new agents or treatment strategies have also been incorporated into combination therapy involving conventional anticancer drugs in several clinical trials, which may help enhance currently available treatment modalities.
However, some puzzling and troubling questions such as whether these treatment strategies induce resistance in tumours and whether they will cause normal cells to die in massive numbers still remain unanswered. This is a true concern if lessons were to be learnt from the conventional anticancer drugs, which wipe out both normal cells and tumour cells and cause brutal side effects and tumour resistance. On the other hand, it would be of clinical benefit, if these molecules that target apoptosis are specifically acting on a single pathway or protein.
However, most of the molecules that enter clinical trials act on several targets and these include many inhibitors of the Bcl-family of proteins and some pan-IAP inhibitors.
Hence, evidence-based long-term follow ups on patients receiving these new cancer treatments are needed and ongoing research should focus on those strategies that can selectively induce apoptosis in malignant cells and not the normal ones. Aging Cell. Breast Cancer Res.
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Reed JC: Bcl-2 family proteins: regulators of apoptosis and chemoresistance in haematologic malignancies. Semin Haematol. CAS Google Scholar. Physiol Rev. CA Cancer J Clin. PubMed Article Google Scholar. Ann NY Acad Sci. The proper formation of heart loops also relies on the process of apoptosis.
Human female oocytes undergo apoptosis during development and after birth. Scientists estimate that seven to eight million oocytes are formed in the fetus , which are reduced to about , oocytes at birth, and then only a few hundred at the onset of menopause.
Apoptosis occurs not only during embryonic development, but also after birth. In humans for example, brain cells undergo apoptosis prior to and following birth to eliminate excess brain cells and streamline nerve impulses.
Apoptosis also occurs in some cells that the body identifies as cancerous to prevent the spread of the cancer and kill the cancerous cells.
However, unregulated apoptosis can cause disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis, which is a motor neuron disease. Keywords: Apoptosis. Apoptosis in Embryonic Development Apoptosis, or programmed cell death, is a mechanism in embryonic development that occurs naturally in organisms. Sources Barres, Ben A. Brenner, Sydney. Clarke, Peter G.
Flemming, Walther. Kiel: Honig, Lawrence S. Kerr, John F.
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