Induction of Apoptosis in Treatment of Cancer Cells Essay Example

homeostasis and development in normal tissues. It leads to removal of unwanted and unnecessary cells to ensure the healthy balance between cell death and cell survival in metazoan. It is important to animals such as long-lived mammals that require to integrate several physiological and pathological death signals.Insufficient apoptosis has been indicated to manifest as autoimmunity or cancer, whereas accelerated cell death occur in chronic and acute degenerative diseases, infertility and immunodeficiency.

Under several stressful conditions such as precancerous lesions, DNA damage activation checkpoint pathway may help to remove DNA damaged cells which are potentially harmful through apoptosis induction to inhibit carcinogenesis. Therefore, the apoptotic signals assist in safeguarding the integrity of genes whereas dysregulation of apoptotic pathways promote tumor genesis as well as rendering cancer cells resistant to treatment.

Hence, apoptosis evasion is the main hallmark for cancer. Cancer cells harbor alterations that lead to impaired apoptotic signaling, hence facilitating development and metastasis of tumor. An overview of mechanisms through which main regulatory molecules regulate apoptosis in regular cells and apoptotic dysregulation models based on alteration of their function that facilities apoptosis evasion in cancer cells has been provided.

Apoptosis defects play critical roles in pathogenesis of tumors allowing survival of neoplastic cells over intended lifespans, the desire for exogenous survival factors is subverted and provision of protection from hypoxia and oxidative stress as the tumor mass grows.it gives time for genetic alterations accumulations that deregulate cell proliferation, promote angiogenesis, interfering with differentiation and increase invasiveness in tumor progression (West, et al., 2014). Apoptosis defects have been considered to be important complements in proto-oncogene activation, as several deregulated oncoproteins promote cell division they also trigger apoptosis for instance

E1a, Cyclin-D1 and Myc.

Defects in chromosome segregation and/or DNA repair usually trigger cell death as a defense mechanism to eradicate genetically unstable cells and these death mechanism defect allow survival of cells that are genetically unstable, provide opportunity to select progressively aggressive clones and also promote tumor genesis. There are various molecular mechanisms with which tumor cells use apoptosis suppression.

Tumor cells become resistant to apoptosis through the expression of ant apoptotic proteins including Bcl-2 or through downregulation or proapoptotic proteins mutation e.g. BAX. The expression of both BAX and Bcl-2 is regulated through the p53 tumor gene suppression.Bcl-2 overexpression occur in different forms of lymphoma human B-cell. This example gives the first and strongest lines of prove that cancer is contributed by failure of cell death.

Apoptosis defects allow survival of epithelial cells in a suspended state, with no attachment to extracellular matrix which leads to metastasis. Resistance to the immune system is also promoted including several weapons of natural killer (NK) cells and cytolytic T cells (CTLs)used to attack tumors that are based on apoptosis machinery integrity (Curcoran, et al., 2013). Defects associated with cancer in apoptosis play an important role in resistance treatment with conventional therapies such as radiotherapy and chemotherapy increasing cell death threshold and therefore need high doses for tumor killing agents.

Thus defective and dysregulated apoptosis regulation is an important factor in tumor biology. Successful elimination of cancer cells through nonsurgical methods is ultimately approached through induction of apoptosis. Thus, all designers of cancer drugs to try either to rectify defective apoptotic mechanism or activated inactivated one. Therefore, all cytotoxic anticancer therapies in clinical use nowadays induce malignant cells apoptosis when they

work. Knowledge on molecular mechanisms of apoptosis their defective stateprovides a room for new class of target therapy.

Proteases called caspases is known to cause apoptosis by specifically targeting cysteine aspartyl. After receiving some signals which are specific instructing the cell to undergo apoptosis several distinctive changes take place in the cell. Protein family referred to as caspases normally activated in apoptosis early stages. These protein cleave important cellular components which are required for cells to function normally such as structural proteins in nuclear proteins and cytoskeleton. For example DNA repair enzymes.

Also caspases can activate some degradative enzymes like DNases, which start DNA cleavage at the nucleus. Distinctive morphology is usually displayed by apoptotic cells during apoptotic process. Normally the cell begin by shrinking following actin filaments and lamins cleavage in cytoskeleton. Chromatin undergo apoptotic breakdown in the nucleus which results in nuclear condensation and a horse shoe like appearance.

Cells shrink and package themselves in a form that can be removed by microphages. The phagocytic cells have the role of clearing apoptotic cells from tissues in tidy and clean fashion to prevent the various problems linked to necrotic cell death.Apoptotic cells phagocytosis through microphages is promoted by changes in plasma membrane caused by macrophage response.(Knizhnik, et al., 2013). One of these changes is the phosphatidyserine translocation to the outer surface of the cell from inside. The last stages of apoptosis are usually characterized by the appearance of small vesicles known as apoptotic bodies or blebs and blisters process.

Caspases in apoptosis mechanism are the real workers. The family of caspases is made up of intracellular cysteine proteases, which work with proteolytic cascades. These caspases activate both themselves and

each other. During proteolytic cascades, caspases may be positioned as either downstream effectors or upstream initiators of apoptosis. There exists many pathways for caspases activation.

First, there are 30 tumor necrosis factor (TNF) members, family receptors; 8 of these contain death domain (DD) in their cytosolic tail. Some of the DD containing TNF-family receptors use activation of caspases as a signaling mechanism, such as Fas/APO1/CD95, CD120a, DR3/Apo2/Weasle, TNFR1/CD120a, DR6, DR%/TrailR2, and DR/TrailR1. Receptors ligation at the cell surface lead to recruitment of various intracellular proteins, such as procaspases on the cystolic domains of receptors which form DISC that lead to activation of caspases resulting in extrinsic apoptosis pathway. Especially caspases 8 and at times caspases 10 are summoned on the DISC.

The caspases contain (DEDs) death effector domains in their N terminal that bind to DED in protein adaptor, FADD, hence linking them to death receptor complexes the TNF-family. Second, the intrinsic pathway were mitochondria induces apoptosis through production of cytochrome-c (cyt-c) in cytosol. Cytochrome which has been released assembles a multiprotein apoptosome .Apoptosome oligomerizes upon binding cyt-c and therefore, bind procasspase-9 through interaction with its caspases recruitment domain (CARD).

Activation of intrinsic pathway is done by myriad stimuli such as oxidants, growth factors, microtubule targeting drugs, DNA damaging agents, oncogene activation and Ca2+ overload (Zhang, et al., 2013). Additionally, mitochondria releases OMI (HtrA2), AIF, endonuclease G and IAP antagonists SMAC (DIABLO).Some of these molecules promote nonapoptotic cell death.

Third, apoptosis induction pathway is specific to NK and CTL cells, which produce apoptosis inducing granzyme B (GraB), protease onto target cells. GraB piggybacks to cells through mannose-6 phosphate receptors (IGFR2) and enter cellular compartments through perforin channels. GraB is serine

protease however, it is similar to caspases, as cleaves substrate at ASP residues.

Fourth, the caspases activation pathway which is linked to Golgi stress and/ endoplasmic reticulum (ER), but mechanistic details are lacking. Lastly, nuclear pathway, which depend on nuclear organelles for apoptosis regulation known as nuclear bodies (NBs) or pml oncogenic domains (PODs).Apoptosis promoting proteins are localized to PODs such as Zip kinase, par4 and Daax, defects in assembly of the nuclear structures are documented in cancers. There is no known explanation to how PODs are linked to caspases activation pathways.

Some endogenous antagonists of caspases activation pathways are discovered and dysregulation of their function or expression in cancers has been identified (Pierotti, et al., 2013). Apoptosis mediators assist cells in deciding successful and unsuccessful apoptosis. Sometimes they act as targets for drug discovery, with an idea of abrogating their cytoprotective functions to restore tumor cells apoptosis sensitivity.

Apoptosis inhibition and inactivation of apoptosis promoters is seen in human cancers. In addition, apoptotic defects translate into resistance in drugs in cancer. Several validation and discovery of various types of cancer therapies have been made. This therapeutic trials act to ensure promising apoptosis inducing agents with high hopes to manage cancer resistance to conventional treatment. This therapeutics are either used in combination or alone.