Molecular Targets and Drug Design: Apoptosis - Essay Example

? Apoptosis 21st December Apoptosis Apoptosis also defined as programmed cell death or physiological cell death that occurs as a result of a deliberate activation of the constituent genes, whose main function is to cause its own death. It is a series of Biochemical events lead to change in the cell morphology followed by cell death. Characteristically these morphological changes includes, the aggregation of chromatin together with cytoplasm and nuclear condensation into a distinct membrane bound vesicles which are known as Apoptotic Bodies, there is chromosomal DNA fragmentation, shrinkage of cell and cell blebbing (which are intact membrane vesicles). There is no inflammatory response, the cellular blebs and remains are quickly phagocytysed by the macrophages and the adjacent cells. (Kumar and Clark, 2005). In an average adult human about 50-70 billion cells die in one day in various tissues like intestines and bone marrow, while approximately 20-30 billion cells die each day in an average child of about 8-14 years. These dead cells are replaced by the new ones. There are 100 trillions cells in our body which are members of a highly organized community which efficiently controls both the cell division and cell death. In simple when a cell is no longer of any use or it become a threat to the body then it undergoes a suicidal programmed cell death mechanism called apoptosis. (Hall and Guyton, 2006). German scientist named Carl Vogt in the year 1842 was the first one to define the main principle of apoptosis. Research about apoptosis has increased greatly since early 1990’s. If apoptosis occurs in excess it results into atrophy while if it is taking place insufficiently then it causes an uncontrollable cell proliferation resulting in cancer. In contrast to Necrosis (traumatic cell death) where the cell swells up due to injury resulting it to burst and spills its contents, resulting in inflammation and injury to an adjacent cells. The process of apoptosis involves a particular proteolytic cascade that causes the cell to shrink become condense, loose its cytoskeleton , alters the cell surface in order for the neighboring phagocyte cells such as macrophage to attach itself to the cell membrane and engulf the cell before the contents spills, thus leaving the adjacent cells healthy.(Hall and Guyton, 2006 ). The process of apoptosis needs energy in the form of Adenosine tri phosphate (ATP) and many Ca+2 and Mg +2 dependant nuclear system are activated which specifically splits the nuclear DNA at inter-histone residues. The endonuclease destroys the DNA following the apoptosis This process involves an enzyme called as CASPASE ( Cysteine-containing Aspartase- Specific Protease) this enzyme is synthesized within cell and stored in it in the form of pro-Caspases, this enzyme once activated result in the cascade of break down of proteins within the cell. Caspase in turn activates the CAD (Caspase DNase) / ICAD( inhibitor of CAD) system that can cause DNA destruction.(Kumar and Clark, 2005) The cells then detach it self and its remains are rapidly eaten up by the adjacent phagocytic cells. There are two main signaling pathways that starts the process of apoptosis :Extrinsic pathway, that is initiated by the death receptors on the surface of cell, these signals include toxins, hormones, growth factors, cytokines and nitric oxide, they either cross the plasma membrane or transduce in order to produce a response. These signals may either trigger or repress the apoptosis. While the Intrinsic pathways initiates at the mitochondrial level. The cell starts intracellular pathway in response to the following trigger’s , stress that may result in cell suicide, binding of the nuclear receptors by glucocorticoids, nutrition deprivation, viral infection, heat, radiation, hypoxia and increased level of intracellular calcium. The Extrinsic Pathway helps in the process of tissue remodeling and to induce immune self tolerance. Now the activated receptors containing internal death domain complexes multiplies the pro-Caspase 8 who’s autocatalytic activity causes the release of the initiator Caspase 8. The Caspase 8 in turn cleaves the Caspase 3 and Pro-Caspase 3, along with other Effector Caspases, causing DNA cleavage, condensation and fragmentation of cells. The Intrinsic pathway depends on the release of Cytochrome C from mitochondria. The Cellular stress like the withdrawal of growth factor or the arrest of p53 cycle which is a potent inducer of apoptosis, initiates the expression of the Bcl-2 (pro-apoptotic) family of proteins, Bak and Bax. These complex attaches to the outer membrane of mitochondria, imbeds and produces permissive pores. Once this Cytochrome C is released it binds to the Apaf-1 (apoptotic protease activating factor) and ATP, which in turn binds to the Pro-Caspase 9 in order to form a protein complex called as Apoptosome. This Apoptosome then activates an initiator Caspase 9. Caspase-9 then in turn activates the Effector Caspase, the Caspase 3. (Kumar and Clark, 2005, ) There is a link between the two pathways, in which the Caspase 8 cleaves the Bcl-2 family, t Bid, which aids the formation of Bcl-2/Bax/Bak pore complex. If this complex is formed predominantly from the Pro-Apototic members of the Bcl-2 family then the Apoptosome / Caspase 9, together with mitochondrial Anti- IAP’s amplifies the effectors Caspases 3 apoptotic activation. However, over expression of anti-apoptotic Bcl 2 proteins will inhibit the intrinsic pathway and it may also dampen extrinsic apoptotic signaling. (Kumar and Clark, 2005) There is another way of self destruction of cells seen in neurons and some other cells achieved by apoptosis induced factor (AIF) .this unlike the above mentioned pathways do not use caspase enzyme. AIF is a normal protein located in the intermembraneous space of mitochondria. When the signal is received by the cell informing that it is the time to die the AIF is released by the mitochondria, migrates into nucleus, binds to DNA, initiate the destruction of the DNA followed by cell death. In general apoptosis produces advantages during life cycle of an organism. For instance, the separation of finger and toes in a fetus occurs as a result of apoptosis of cells between the fingers. As a result of apoptosis only about half of the nerve cells that are located in a newly born baby’s brain are able to create connections to rest of the brain cells, instead of clustering around a developing brain. Elimination of T cell which otherwise may create an auto immune attack against the body itself is achieved by apoptosis. Regulated apoptosis is necessary for various processes of life, which includes the formation of tissue structure in embryogenesis, wound healing and auto destruction of the thickened endometrium in a normal menstrual cycle. It is also used in cancer treatment, chemotherapy and radiotherapy regimens, they work by triggering tumor cell self apoptotic pathway. According to recent studies, the abnormalities of apoptosis can play a chief role in Disease like neurodegenerative Alzheimer’s disease, in autoimmune diseases and in various types of cancer. Some chemotherapeutic medicines have been seen to cause apoptosis in cancer cells. (Hall and Guyton,2006). The main method of treatment used in death signaling related diseases can be achieved by either increasing or decreasing the apoptosis in the affected cells. On the other instance if there is a complete loss of control over the cell death (causing excessive apoptosis) it can lead to hematologic and neurodegenerative disease and tissue damage. Virus also causes the induction of apoptosis in the living cells of human being by series of mechanism such as, receptor binding, activation of the protein kinase R, interaction with the p53, viral proteins binds to the MHC proteins on the surface of the viral infected cells, that causes the cells of the immune system that is the cytotoxic cells and natural killer cells to identify it and then causes the viral infected cell to undergo the process of apoptosis. The progression of HIV disease is closely linked to an excessive and unregulated process of apoptosis. In a normal healthy individual the amount of CD4+ is in balance to the cells that are produced by the bone marrow, but in HIV patients the ability of the bone marrow to regenerate the CD4+ cells is compromised thus resulting in the loss of this balance. In case of HIV there is an increased death rate of CD4+ lymphocytes by an uncontrollable process of apoptosis. Treatment that aims to inhibit apoptosis works by inhibiting the expression of pro apoptotic factor and enhance the expression of anti apoptotic factor. The progression of AIDS occurs mainly due to the depletion CD4+ helper lymphocytes in a very rapid manner and therefore cannot be replenished by the bone marrow leading to immune compromise body. One of the ways by which the depletion of Helper T lymphocytes is achieved is through apoptosis. The Fas- induces apoptosis which might be blocked by using FLIPs( FLICE-inhibitor proteins, that inhibits caspases 8 and caspases 10), Bcl 2 (which prevents the release of cytochrom c and subsequently causes the activation of caspases 9)and Crm A (that is a cytokine response modifier A). Enhancing the amount of IAPs works to achieve the blockage of specific type of caspases and ultimately, the Akt protein kinases enhances the cell survival via two pathways. One is achieved by Akt phosphorylates and inhibits the Bas, causing Bas interaction to the scaffold causing in the dissociation of Bcl and thus allowing the cell survival. Akt also leads to the activation of NF-kB causing cell survival. This activated NF-kB then causes the expression of anti apoptotic gene like Bcl 2, causing inhibition of the process of apoptosis. This NF-kB plays a vital role in both pro and anti apoptotic role depending upon the stimulus used and the type of cell. In the year 2007 a new way to suppress apoptosis was presented in a research in a journal of clinical investigation that indicated an over expression of a chromosomal protein belonging to high mobility group protein A1 (HMGA1) that can lead to suppression of p53 which is a tumor suppressor gene by simply shutting its activated protein out from the nucleus of the cancerous cells. It is observed that p53 regulates the growth of a cell by the process of apoptosis and can decrease the size of a tumor when it is reactivated. (Gawrylewski, 2007) Cancer is well known as malignant neoplasm. It is caused by genetic mutation within a single affected cell. The genes which are most commonly affected are those which control the cell cycle check points, the DNA repair and damage recognition, apoptosis, growth signaling and differentiation. The proliferation might continue to occur at the expense of differentiation, thus this together with the failure of apoptosis leads to the formation of a tumor along with the growth of abnormal cells which are varying in size, shape and nuclear morphology. In cancer the cells grow uncontrollably resulting in the formation of malignant tumor. They might invade the nearby body parts and spread via the lymphatics and blood stream to more distant part of the body. (Kumar and Clark, 2005).Cancer is principally a disease of failure of tissue growth regulation. For a transformation of normal cells to cancerous cells, the cells which regulate the cell differentiation and growth have to be altered. (Hall and Guyton , 2006) The difference between a cancer cell and a normal cell are: firstly, the cancer cells do not have usual cell growth limitation mainly because they don’t need all the growth factors that are required by a normal cell. Secondly, the cancer cells has a less adhesive property as compared to a normal cell, thus they have the ability to quickly travel via blood stream to other parts of the body, multiplying rapidly thus causing new cancerous growths. Thirdly some cancers are responsible to produce an Angiogenic factor that allows large amount of new blood vessels to grow at the sight of cancer, therefore supplying the nutrients required for the growth of cancer cells. Thus in short cancerous tissues compete with the normal tissues to acquire nutrients. The proliferating ability of cancer cells which keep on multiplying everyday thus their nutritive demand increases which end up into the death of normal tissues. (Hall and Guyton, 2006) The common causes of cancer are tobacco consumption , alcohol consumption , alkylating agents which causes cancer of bladder and bone marrow, estrogens causing endometrial,vagina and breast cancer and androgens hormones causing prostrate cancer, radiotherapy, excessive fat accumulation resulting in obesity causing colorectal cancer, some environmental causes includes vinyl chloride causing liver cancer, polycyclic hydrocarbons causing skin, lung ,bladder cancer and myeloid leukemia, aromatic amines causing bladder cancer, asbestos causing lung cancer, Ultraviolet light causing skin and lip cancers, Ionizing radiations ( such as X rays, Gamma rays ) causing leukemia and thyroid cancer, Melanoma they avoid apoptosis by inhibiting the Apaf-1, Afla toxin causing liver cancer, some viruses like Hepatitis B, hepatitis C causing Hepatocellular carcinoma, Human T cell leukemia virus causing leukemia and lymphomas, Ebstein barr virus associated with burkitt’s and hodgkin’s lymphomas, produces proteins similar to Bcl 2 and another protein that increases the production of Bcl 2 results in making cell more resistant to Apoptosis. Human Papilloma virus that causes cervical cancer in this the virus produces a protein E6 that binds and inactivates the p53. While others are Schistosoma Japonicum causing bladder cancer , Helicobacter pylori associated with stomach cancer.(Kumar and Clark, 2005).In many cases of cancer these is a strong family history. The kinetic of the cancer cells in human are highly variable. Mutation occurs commonly in those genes which control a series of intracellular proteins, the cyclin and cyclin dependent kinases and also oncogenic products that regulate the proliferation. The genes which are affected can be divided into two broad categories one is Oncogenes that is responsible to control growth and the reproduction, while second is Tumor Suppressor Gene which inhibits the process of cell division and survival. Thus malignant transformation can be a result of formation of novel Oncogene which is an inappropriate over expression of the normal Oncogenes or it may be caused by it’s under expression or simply by disabling tumor suppressor genes. The proliferation might become abnormal as a result of defect in nuclear enzyme telomerase or because of getting in contact with other cells, cytokine signaling and nutrient supply. The continuous activity of telomerase will help in maintaining the neoplasmic state in the cancer cells. (Kumar and Clark, 2005) In various human epithelial tumors the epithelial growth factors and its receptors are over expressed resulting in non restraining growth of such tumors. Transforming growth factor TGF beta, which is a cytokine affects the extracellular matrix proteins, the angiogenesis and also the over expression of immune effector cells are seen in tumor cells. Such defects in TGF beta signaling has been observed in cancer cells. Abnormality in the tumor suppressor genes, MADH4 and p53 occur in condition such as pancreatic cancer. Only a small quantity of cells that mutate in the body leads to cancer. There are various reasons for this; firstly most cells that mutate have a very small life span and simply die. Second, out of the mutated cells there are only few of them which survive and become cancerous because most of these mutated cells have a normal feed back mechanism that inhibits excessive growth. Thirdly, those cells which are likely to be cancerous are frequently destroyed by the body self immune system prior to them becoming cancerous. This is achieved by the mutated cells by forming an abnormal protein in their cell due to their altered genes, these proteins in turn activates the body self immune mechanism resulting it to form antibodies and lymphocytes that fights against cancerous cells and kills them. It is therefore seen that the risk of cancer is five times more in the individuals whose immune system is suppressed or are on immune- suppressing medicines after a kidney or heart transplantation. Fourthly, various activated Oncogenes are needed to cause cancer. For example one such gene may result in a rapid reproduction of a cell line but no cancer results due to absence of a mutant gene in order to form the required blood vessels. (Hall and Guyton, 2006) An essential method of cancer treatment is Inhibition of angiogenesis, as formation of new blood vessels around tumor not only supplies it with oxygen and nutrients but also allows the hematogenous spreading of the cancer. (Kumar and Clark, 2005) Billions of cells die each day by a highly active, well organized and regulated mechanism of cell death known as Apoptosis. In which there is a series of biochemical events causing the change in the cell morphology followed by cell death. In brief when a cell is no longer of any use or if it becomes a threat to the body then it undergoes a suicidal programmed cell death mechanism called Apoptosis. This occurs in response to various physiological and pathological stimuli. It is mediated within the cell by the enzyme known as Caspases. Disturbance in this normal balance of the large number of proteins causes the survival of tumor cells over their normal counter part. If the process of apoptosis occurs in excess it causes atrophy, but if it takes place insufficiently then it results into an uncontrollable process of cell proliferation causing cancer. For a normal cell to transform into a cancerous cell, the cells which are responsible to regulate the process of cell differentiation and growth have to be altered. The Apoptosis plays a vital role in a life cycle of a human being causing the intrauterine separation of fingers and toes, the process of endometrial shedding (menstruation), elimination of T cell, and it is also used in chemotherapy and radiotherapy where it works by triggering a tumor cell self apoptotic pathway making apoptosis one of the most essential processes of life. Bibliography GAWRYLEWSKI, ANDREA (9TH February, 2007). A new way to suppress apoptosis. Thescientist.com. Viewed on 20th December 2012, from http://www.thescientist.com/?articles.view/articleNo/24746/title/A-new-way-to-suppress-apoptosis-/ HALL,JOHN AND GUYTON ARTHUR (2006, p. 40). Suicidal programmed cell death mechanism . Medical Physiology. Philadelphia: Elsevier Saunders. HALL,JOHN AND GUYTON ARTHUR (2006, p. 40). Process of apoptosis. Medical Physiology. Philadelphia: Elsevier Saunders. HALL,JOHN AND GUYTON ARTHUR (2006, p. 40-41).Role of apoptosis in cancer, autoimmune diseases and neurodegenerative diseases. Medical Physiology. Philadelphia: Elsevier Saunders. HALL,JOHN AND GUYTON ARTHUR (2006, p. 41). Difference between a normal cell and a cancerous cell. Medical Physiology. Philadelphia: Elsevier Saunders. HALL,JOHN AND GUYTON ARTHUR (2006, p.41).Cancer. Medical Physiology. Philadelphia: Elsevier Saunders. KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.162). Define Apoptosis? Clinical Medicine. Edinburgh, New York: Elsevier Saunders. KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.163).Process of apoptosis .Clinical Medicine. Edinburgh, New York: Elsevier Saunders KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.163).Extrinsic and Intrinsic pathways of apoptosis .Clinical Medicine. Edinburgh, New York: Elsevier Saunders KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.485).Biology of cancer? Clinical Medicine. Edinburgh, New York: Elsevier Saunders KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.484).Common causes of cancer? Clinical Medicine. Edinburgh, New York: Elsevier Saunders KUMAR ,PARVEEN AND CLARK, MICHAEL (2005,p.485).Kinetics of cancer.Clinical Medicine. Edinburgh, New York: Elsevier Saunders PINES, MAYA (2002), How apoptosis brings good health: the virtue of cell suicide, Viewed on 20th December 2012, from http://www.hhmi.org/genesweshare/c110.html Read More