1777365195580
Qualification Higher National Diploma in Biomedical Science
Level 5
Module Name Biology Of Disease
Module Number BIOM 517
Name of Candidate Sukeshana Ahileswaran
Student Number 515101702
Submission Date 5th November 2018
Word Count Content
Introduction
There are two types of cell death – Necrosis and Apoptosis. Necrosis can be envisioned as a nonspecific swelling of cells and its membrane organelles that result in disrupting of their integrity. A crucial if cell necrosis occurs in the body of the multi cellular creature it leads to development of inflammatory process. But in programmed cell death is that usually the plasma membrane preserves its integrity and the cells remains can be engulfs either by local macrophages or neighboring cells. Physiological cell suicide process is termed apoptosis / programmed cell death. Cells that kill themselves by implementing this process typically exhibit a characteristic morphology. The term apoptosis (a-po-toe-sis) was first used in a classic paper by Kerr, Wyllie and Currie in 1972 to describe a morphologically distinct form of cell death, although certain components of the apoptosis concept had been clearly described many years previously. This is probably one of the most widely studied subjects among cell biologists. Apoptosis occurs normally during development and aging and as a homeostatic mechanism to maintain cell populations in tissues. Apoptosis also occurs as a defense mechanism such as immune reactions or when cells are damaged by disease or noxious agents.

Understanding apoptosis in disease condition is very important to leave clues on how the disease can be treated. In cancer apoptosis evolved as a rapid and reversible process to efficiency eliminate not operating normal cells. A characteristic of cancer is the ability of malignant cells to evade apoptosis. In cancer here is a loss of balance between cell division and cell death and cells that should have died did not receive the signals to do so.

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The problem can arise in any one step along the way of apoptosis for an example: down regulation of p53, a tumors suppressor gene which results in reduced apoptosis and enhance tumor growth and development and inactivation of p53 regardless of the mechanism has been linked to many human cancers. Inhibition of apoptosis does not rapidly transform cell or cause cancers. Hence apoptosis plays an important role in both carcinogenesis and cancer treatment.

Apoptosis
Morphological changes:
An apoptotic cell death concerns both the nucleus and the cytoplasm is remarkably similar across cell types and species. Morphological symptoms of apoptosis in the nucleus are chromatin condensation and nuclear fragmentation which are accompanied by rounding up of the cell, reduction intracellular volume and retraction of pseudopodes. Then karyorrhexis occurs: chromatin condenses until it breaks inside a cell with an interact membrane. At the later stage some of the morphological features include membrane blebbing, ultra structural modification of cytoplasm organelles and a loss of membrane.

Biochemical changes:
Generally three types of biochemical changes are occur under the apoptosis. They are activation of caspases, degradation of DNA by endogenous DNases and membrane change and recognition by phagocytic cells.

Mechanism of Apoptosis:
There are two different phase in apoptosis. They are initiation and the execution phase. The initiation phase is quite complex and involves many different proteins. This process started by various stresses from either extracellular or intracellular. The initiation phase induces the execution phase. The execution phase involves in the activation particular enzymes (caspases and others) that directly lead to the cell death.

There are two major apoptotic pathways termed as intrinsic and extrinsic. This intrinsic pathway is controlled by BCL-2 family members that act by triggering BH3-only family proteins which activates proapoptotic effectors BAX and BAK. These proapoptotic effectors influence the mitochondrial membrane that ensues in the release of cytochrome c that forms a complex ‘apoptosome’. This complex consists of caspase-9, Apaf-1 and cytochrome c which activates effector caspases and executes apoptosis. The released protein second mitochondria-derived activator of caspases (SMAC) blocks the caspase inhibitor called X-linked inhibitor of apoptosis protein (XIAP). On the other hand, extrinsic/death receptor-mediated apoptosis is engaged when certain death receptor ligands, such as FAS ligand and TNF, tie up their death receptors with the plasma membrane, thereby activating caspases-8 via FADD and TRADD. These two pathways congregate at the effector caspases (caspase-3, -6 and -7). Generation of tBID by caspase-8 in death mediated pathway could engage intrinsic pathway and magnify the apoptotic response.

Alternatively, activation of these caspases is also brought about by the formation of death receptor (DR) signalling, initiated by DRs at the cellular surface. Initiation and execution of apoptosis via this pathway is referred to as ‘extrinsic’ or ‘death receptor’ pathway. All the members of DRs are expressed on the cell membrane and are characterized by the presence of a death domain (DD) that plays a crucial role in apoptotic signal transduction. So far, six members of DR family have been recognized: TNF-R1, CD95 (APO1/FAS), DR3, TRAIL-R1, TRAIL-R2 and DR6, TRAIL receptors (TRAIL-R1 and TRAIL-R2) are promising targets for cancer therapy. This extrinsic apoptotic cell is introduced by signals originating from these cell-surface DRs activated by death ligands. This triggering of DRs by death ligands ensues in the formation of a death-inducing signalling complex (DISC). This DISC consists of oligomerized receptors: the DD containing adaptor molecule called Fas-associated death domain, procaspase-8 (FLICE), procaspase-10 and the cellular FLICE inhibitory proteins (c-FLIP). Formation of DISC activates procaspase-8/10 and subsequently initiates proapoptotic cascade of caspases.

Figure 1: The mitochondria – mediated intrinsic (a) and death receptor – mediated extrinsic (b) pathway (Baig et al., 2016).

Cancer and apoptosis
Apoptosis is one of the checks and balances built into the cell cycle. Normally when something goes wrong in a cell, it is quickly destroyed via apoptosis. This safeguard helps prevent the development of cancer. For example, when skin cells are damaged by ultraviolet radiation (i.e. sun, tanning beds) apoptosis is normally triggered. This helps eliminate any badly damaged cells. If apoptosis does not occur, these damaged cells may survive and develop into cancerous cells. Apoptosis also plays a role in a progression. For a cancer cell to move to another part of the body (metastasize) it must be able to survive in the blood or lymphatic systems and invade foreign tissue. Normally apoptosis would prevent these things. Cancer cells are able to evade apoptosis and continuously divide despite their abnormalities. Tumors that remain in one place and do not appear to spread are known as “benign tumors”.Malignant tumors, the more dangerous ones, spread to other parts of the body either through the bloodstream or the lymphatic system.

Figure 2: Mechanism contributing to evasion of apoptosis and cancer
P53 Gene
This is the most commonly muted gene in human cancers, but precisely how if prevents. Tumors developing are not certain human heterozygous for loss of function to P53 and mice with one or both alleles of this gene develop cancers at an early age in many different tissues. P53 has two main functions, it can cause cell cycle arrest by transcriptionally activating the P21 cyclin kinase inhibitor gene and it can cause apoptosis by transcriptional activationg pro apoptosis gene especially for the BH3 protein (Gerl and Vaux, 2005).

There are many types in cancer occurs due to the mistakes in the mechanism of apoptosis.

Breast cancer
Breast cancer is a malignant tumor that starts in the cells of the breast. Damage to the DNA and genetic mutation can lead to breast cancer have been experimentally linked to oestragen exposure. Those with a family history of ovarian or breast cancer are high risk in to breast cancer. Breast cancer might be a result of failure of such an effective immune defense and surveillance.

HER2 is transmembrane receptor tyrosine kinase that activates multiple growth promoting signaling pathways including PI3K-AKT and Ras – MAPK. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There have been much investigation into mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical target for HER2as these positive breast cancers as these cancer often become resistant to therapies that directly target HER2.

Apoptosis occurs in the breast cancer by the process given below.

HER2 activates PI3K-AKT signaling which need for the mechanisms HER2 uses to suppress apoptosis. Over expression of HER2 increase in anti apoptotic Bcl-2 proteins. It also inhibits P53 mediated apoptosis by up regulated of MDM2 by activation of AKT. And caspase activation also inhibited by HER2. And HR2 can directly involve into the apoptosis by translocation to the mitochondria to inhibit cytochrome c release.

Figure 3: HER2 suppresses apoptosis through mechanisms in both extrinsic and intrinsic pathway.

Ovarian Cancer
This is a type of cancer which begins in ovarian. The female reproductive system contains two ovaries, one on each side of the uterus. They produce eggs and as well as the hormone oestragen and progesterone.

Ovarian cancer often goes undetected until t has spent with the pelvis and abdomen. At this final stage ovarian cancer is most difficult to treat and is frequently fatal.

Figure 4: Proliferation of cancer cells in the ovarian
The apoptosis pathway of the ovarian cancer is given below.

Apoptosis results from caspase activation brought upon through two separate pathways. Since the intrinsic pathway is commonly disrupted in cancer cells, targeting the extrinsic pathway by ligand-activation of cell-surface death receptors is regarded as a promising strategy to overcome apoptosis resistance. The recombinant human form of the TNF-family member TRAIL and other drugs directed at its agonistic receptors DR4 or DR5 induce apoptosis in a wide. Variety of human cancer cell lines and their xenografts, including ovarian carcinoma cells, without being toxic to normal tissues. 
Lung cancer
Lung cancer is the uncontrolled growth of abnormal cells that start off in one or both lungs; usually in the cells that line the air passages. As tumors become larger and more numerous, they undermine the lung’s ability to provide the bloodstream with oxygen. When cancer spreads it is much harder to treat successfully. Primary lung cancer originates in the lungs, while secondary lung cancer starts somewhere else in the body, metastasizes, and reaches the lungs. They are considered different types of cancers and are not treated in the same way.

Chronic inflammation and fibrosis due to tuberculosis can induce genetic mutation. Parenchyma tissue of lung is involved in both disease of TB and lung cancer. The induction of apoptosis especially in patients with immune deficiency may result in increasing cytokines which will either reduce the activity of P53 gene or enhance the activity of Bcl-2 and cause the inhibition of caspase-3 due to the expression of mitochondria cytochrome oxidase. These process leads to the abnormal proliferation of cell in the lung (Masoud and Keikha, 2018).
Targeting apoptosis in cancer treatment
Every defect abnormality along the apoptotic pathways may be also is an interesting target of cancer treatment. There are many treatments going on by targeting the factors which induce the apoptosis that leads to cancer.
Therapeutic method Remarks.

Targeting the Bcl2 family
Drug oblimerson sodium which is a Bcl2 antisense oblimer the first agent targeting Bcl2 to another clinical trial. The drug has been reported to show chemosesitive effects in combined treatment with conventional anticancer drug in chronic myeloid, leukemia patients and an improvement in survival in these patients.

P53 – based drug Therapy
Class of drugs that can restore be mutated P53 back to its normal function. For an example: Phikan 083. There are many drugs which have been found to intercalate with DNA and de stabilize the DNA. P53 DNA domain complex resulting in the restoration of unstable P53 mutants, stabilize P53 selectively induce senescence in the cancer cells and resulting in inhibitor of cell metastasis. Such as CP-31398, nutlins and MI-219
P53 – based immunotherapy
One of the types of treatment has been carried out using the P53 vaccine.

Caspase – based drug therapy
‘Apoptin’ is caspase inducing agent which synthesize from chicken anemia virus and had the ability to selectively induce apoptosis in malignant but not normal cells. Another class of drugs is the kind of the peptides which contains the arginine – glycine aspartate motif. They have an ability to induce auto activation of pro-caspase- 3 directly. They have also been shown to decrease the activation threshold of caspases or activation capase, contributing to an increase in drug sensitivity of cancer cells
Caspase gene therapy
Human caspase 3 gene therapy was found to induce extensive apoptosis and reduce tumor volume. It 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.
Table 1: Different types of therapeutic methods against to cancer.

Conclusion
Finally, Apoptosis targeted cancer therapy has been an essential approach in combating this deadly cancer however we are still left with huge challenge to overcome. Development of drugs that either any blocking the action of anti apoptotic proteins such as IAPS, small molecule inhibitors. There is no qualm in the fact that our understanding of mechanistic pathways and their interaction with others has advanced considerably in last 20 years, but fact that we have not been able to demonstrate our win in the battle against cancer questions our current strategies adopted to address cancer in near future. Responses to DNA damage have been shown to play crucial roles in responding against stresses that stimulate abnormal functions or cause DNA damage. Manipulation of this already existing mechanism could prove to be an interesting target in cancer therapeutics, owning to the fact that major decisions of cell survival and death decided by the response system.
In my opinion,