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What causes cancer?

Discuss about the Cancer Cell lines Drug Discovery and Development.

Cancer results from a cascade of molecular pathways that alter the characteristics of normal cells. While understanding the biology of cancer, it is caused when cells inside the body accumulate due to genetic mutations that interfere with normal cell properties. Cancer cells prevent the invasion and cell overgrowth where mutated cells divide and grow without any specific signals (De Martel et al. 2012). As these cells divide, they gain new characteristics including structural changes, new enzymes production and decrease in cell adhesion. This heritable change makes the cells and its progenies to grow and divide inhibiting the growth of the surrounding cells. As a result, they spread and start invading cells in proximity. Cancer cells are malignant in nature that spread or invade to other parts of the body through blood or lymph forming new tumours distant from the original site. Unlike these tumours, benign tumours do not invade or spread to other nearby tissues and large (Meacham and Morrison 2013).

Cancer cells differ from normal cells as they have uncontrollable growth rate and invasive in nature. Normal cells are distinct and specialized to perform specific functions where cancers cells are not specialized making them divide unstoppably. Cancer cells grow continuously forming a cluster called tumour having growth factor proteins that make them grow continuously. Another difference between cancer and normal cells is that the latter does not responds to signals to top growing. Moreover, they do not repair or undergo apoptosis or die when they get old or damaged. Cancer cells lack adhesion molecules that make them float and travel to distant body arts via bloodstream or lymph gaining the ability to metastasize (Vogelstein et al. 2013). When they reach new regions like lungs, lymph nodes, bones or liver, they start growing and form tumours at the secondary locations. In contrast to normal cells, there is variability in cancer cell size as they are larger with abnormal shape, nucleus or cell organelles. The nucleus appears darker and larger containing excess DNA having abnormal chromosomes arranged in disorganized manner.

Only small proportion of 35,000 human genes is associated with cancer and alterations in these genes are associated with various cancer forms.  This malfunctioning is broadly divided into three groups: proto-oncogenes, oncogenes and tumour suppressor genes. Proto-oncogenes in normal cells code for proteins that send signals for cell division to the nucleus initiating signal transduction pathway. This cascade comprises of membrane receptors for signalling and intermediary proteins that carry signal to cytoplasm and transcription factors activate cell division genes in the nucleus. However, altered versions of proto-oncogenes give rise to oncogenes activating signals stimulating uncontrolled growth. Proto-oncogenes like RAS, MYC, WNT, TRK and ERK acquire activating mutation that form tumour-inducing molecule called oncogene through three activation methods involving gain-of-function mutation (Hnisz et al. 2016). Point mutations occur in proto-oncogenes result in constitutively protein product. Gene amplification or localized reduplication of DNA segment in proto-oncogene also leads to overexpression of protein. Chromosomal translocation results in growth-regulatory gene that is controlled by a different promoter resulting in inappropriate gene expression.

The Differences Between Cancer Cells and Normal Cells

Tumour suppressor genes also play an important role in cell growth and division. They act to inhibit cell proliferation and development of tumour. However, these genes lose control or gets inactivated that remove negative regulators in cell proliferation and contribute to abnormal tumour cell proliferation (Yates and Campbell 2012). Mutations occur in DNA repair genes like mismatch repair (MMR) genes, nucleotide excision repair (NER) group, DNA crosslink repair that results in inherited cancer syndromes. DNA repair mechanism is the backbone of survival; however, decreased efficiency or inactivation occurs by epigenetic gene activation mechanism that affects DNA repair activity of the genes (Jeggo, Pearl and Carr 2016).

Carcinoma cancers begin in tissue or skin that covers the surface of glands or internal organs forming solid tumours. Examples comprises of breast cancer, prostate cancer, colorectal and lung cancer. Sarcoma begins in the connective tissue that connects and supports the body developing in nerves, muscles, fat, joints, tendons, cartilage, blood vessels or bone. Leukaemias are blood cancers that begin when there is change in structure and uncontrollable growth occurs in blood cells. The four main types of leukaemia are acute and chronic lymphocytic leukaemia, acute and chronic myeloid leukaemia. Lymphomas are cancer that begins in lymphatic system causing Hodgkin and non-Hodgkin’s lymphoma. Melanomas are cancers that begin in cells that form melanocytes that are specialized cells synthesizing melanin, pigment that impart colour to the skin causing skin cancer (Sandoval and Esteller 2012). Colon cancer is also a type of adenocarcinoma that is discussed in the subsequent section.

Colon cancer is the large intestine cancer that makes up the final part of the digestive tract. Mostly, colon cancer begins as a benign or non-cancerous clump of cells known as adenomatous polyps. These polyps are small and show few symptoms. They comprise of excess abnormal and normal appearing cells in the glands that cover colon’s inner wall. These abnormal growths later enlarge and degenerate to become adenocarcinomas. This cancer generally occurs before the age of 40 years and due to lifestyle factors. More than 75-95% colon cancers occurs in individuals with no or little genetic risk and out of which 10% is linked to sedentary lifestyle and addictive behaviour (Kandoth et al. 2013). It originates from epithelial cells that lines colon of the gastrointestinal tract due to mutations in Wnt signalling that enhance signalling activity. Colon cancer are acquired or inherited that occur in crypt stem cell of the intestine. Adenomatous polyposis coli (APC) gene is also polyposis 2.5 deleyed protein that is encoded in humans by APC gene. This protein is a negative regulator of beta-catenin concentrations and E-cadherin that play an important role in cell adhesion. This protein prevents the beta-catenin protein accumulation and as a result, it is accumulated to high levels that translocated to nucleus, DNA binding and activates proto-oncogenes transcription (Burrell et al. 2013). Mostly, APC gene is important for cell differentiation and renewal, but at inappropriately high levels, it causes cancer. Apart from Wnt signalling, other mutations also occur that make cells cancerous like p53 gene that monitors cell division. Inherited gene mutations increase the risk of colon cancer that is present in two most common forms. Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome develop in individuals before the age of 50 years. Familial adenomatous polyposis (FAP) is a disorder that greatly increases the risk of colon cancer and develops polyps in the colon and rectum lining (Isik et al. 2014).

Genes Associated with Cancer

Diagnosis of colon cancer is performed through sampling of colon obtained during colonoscopy that depends on lesion location. The cell line acquires mutation where it transforms from benign to invasive epithelial cancer cells. To study the phenotype of colon cancer, it is important to study cell lines that are considered efficient biomedical research tools that emphasize on genotype characterization and authentication (Kreso et al. 2014). There are 24-colon cancer cell-lines that vary in growth characteristics and appearance. They are used to study the biology of colon cancer and test treatments. The established cell lines maintain and represent the genetic diversity of the primary colon cancers. DNA copy number and exome mutation spectra in colon cancer cells closely resemble to hypermutation phenotypes defined by defective DNA polymerase and DNA mismatch repair, proofreading deficiency and concordant mutations altered in Wnt, p53 pathways (Cayrefourcq et al. 2015).

Among all the cell lines in colon cancer, HCT116 and HT-29 is human colon cancer cells that are used in drug screening and therapeutic research. HCT-116 has mutation in KRAS proto-oncogene in codon 3. They are considered suitable transfecting agents or the gene therapy and research. These cell lines possess epithelial morphology that can be used to study the tumorigenicity. They have adherent properties having epithelial morphology having posttive control for PCR mutation assays present in codon 13 (Wang et al. 2013). When these cell lines are transducted with viral vectors that carry p53 gene, there is arresting of HCT116 in the G1 phase. Colony proliferation of HCT116 was inhibited by P85/5-Fu to study the proliferation of colon cancer and corresponding inhibitors. This cell line has two important variations: Insp8 gene having large expression and one without it. This gene plays a role in the metabolism of cell’s energy processing that can in turn also affects the cell phenotype (Sun et al. 2012).

The doubling time of HCT-116 is ~18 hours and is suitable for in vivo and in vitro experimentation in life studies where it forms tumours and metastasize followed by implantation of cells (Kim, Lee and Kim 2013). These cell lines are also beneficial in evaluating the effects of therapies and drugs available with different reporters and facilitate multi-modality imaging. For high and constitutive expression of HCT-116 reporter proteins, generation of cell lines are carried out by lentiviral vector transduction. These vectors are used for carrying out transductions that are self-inactivating (SIN) vectors where there is deletion of viral promoter and enhancer. This results in increase in the biosafety of lentiviral vectors through prevention of mobilization of competent viruses’ replication. These cancer cell lines are genotypic in nature that results in reduced responsiveness over time that ensures performance and stability of the cancer cell lines (Sahlberg et al. 2014). This cell line does not express or differentiates CDX1 or sub-populations of cells having great tumour-forming capacity. This suggests that HCT-116 contains cancer stem cells (CSCs) subpopulations that are characterized by cell surface markers and morphology of colony having self-renewal ability and differentiation into multiple lineages.

Types of Cancer

HT-29 was initially derived from Jorden Fogh, 44-year-old Caucasian female in 1964 is also epithelia in nature having adherent properties. They have a unique model that can be used to study molecular mechanisms of differentiation of intestinal cells. Under appropriate culture media conditions, these cell lines can be manipulated to express enterocyte differentiation. This is the reason HT-29 is considered pluripotent cells that can be used to study molecular and structural events that are involved in colon cancer cell differentiation. This cell line forms tight monolayer that exhibit similarity to the enterocytes in the small intestine. These cell lines increase the production of p53 tumour antigen having a mutation at the 273 position that results in replacement of arginine to histidine (Bogaert and Prenen 2014).


HT29 cell line is used in preclinical research for the differentiation ability and thus mimics real colon cells in vitro successful for research of epithelial cells. HT-29 terminates differentiation into enterocytes replacing glucose by galactose in the cell culture medium. Moreover, these cells have induced differentiation property that is galactose-mediated that causes adherens junction strengthening. These cell lines also proliferate in cell culture media  that lack growth factors with 4 days doubling time, although it can reduced by using fetal bovine serum (FBS). They have high glucose consumption and remain undifferentiated in standard medium (Mouradov et al. 2014). They grow in multi-layer comprising of unpolarised differentiated cells that does not possess characteristics of normal intestinal epithelia cells and low amount of hydrolases. Biochemical markers physiologically and morphologically characterize the polarised phenotype of HT-29 colon cancer cells (Martínez-Maqueda, Miralles and Recio 2015). The differentiation is influenced by growth related factors that starts after confluence forming a monolayer and tight junctions. The brush border of HT-29 contains proteins that are present in normal intestinal microvilli like villin. Moreover, these cells also express hydrolases that are as small intestine; however, enzymatic activity is much lower than normal intestine with no lactase expression.  

HT-29 show relevance to in vivo as there is similar protein expression as human intestinal cells. The significant differences in metabolic and transporters gene expression from the human intestinal cells also affect suitability of HT-29 in showing in vivo permeability. According to Cancer Genome Atlas Network (2012), the expression of 377 genes in this cell line used as in vitro models in epithelium showed that HT-29 differentiation has similarity with human colonic tissues and are not different. However, there are significant advantages and disadvantages of using HT-29 cell line in vitro as summarised by (Wilding and Bodmer 2014). The differentiated phenotype of this cell line is similar to enterocytes of small intestine in regards to structure, cell differentiation process and brush-border hydrolases. The amount of villin expressed in HT-29 differentiated cells shows similarity with freshly prepared colonocytes. On a contrary, they are malignant cells that have high glucose consumption and glucose metabolism impairment. Due to brush-border hydorlases, they do not show any similarity with normal enterocytes. Altogether, HT-29 colon cancer cell lines are considered valuable model for studying the biology of colon cancer cells (Calon et al. 2012).

Colon Cancer

Cancers generally develop resistance to the chemotherapies and there is an increased prevalence of drug resistant cancers. The ability of cancer cells to become resistant is functionally and structurally unrelated to anti-cancer drugs called multi-drug resistance (MDR). Chemotherapy is the treatment given to the patients diagnosed with locally, advanced and metastasized cancer. This poses challenge in administering drug dosage that minimizes treatment toxicity and maximizes efficacy. MDR is multifactorial and follow cellular pathways that are involved in drug resistance in cancer. MDR in cancer is a mechanism where they develop resistance to chemotherapy that results in minimization of cell death and drug-resistant tumours expansion (Kathawala et al. 2015). This problem affects the treatment of cancers posing major challenge to the researchers. This resistance occurs against anticancer drugs and as a result, there is decreased drug uptake, activation of detoxification system, increase in drug efflux, and evasion of apoptosis (drug-induced) and DNA repair mechanism activation.

MDR either acquired or inherent exist against anticancer drugs developed through multiple mechanisms. Drug inactivations that occur in vivo undergo complex mechanisms where drugs interact with different proteins that modify or partially degrade the other molecules leading to activation. In such cases, anticancer drugs undergo metabolic activation that acquire efficacy. Due to decrease in drug activation, cancer cells may develop resistance to chemotherapies. Many anticancer treatments demand metabolic activation and therefore cancer cells may develop resistance through change in proteins that are related to apoptosis. For example, p53 gene is mutated in half of cancers where deletion or mutation of this gene results in non-functional form that results in MDR. On a contrary, p53 regulators inactivation like apoptotic protease activating factor 1 (Apaf-1) and caspase-9 and cofactors can result in drug resistance (Kibria, Hatakeyama and Harashima 2014).

Another mechanism is alteration of drug targets takes place due to modifications in expression levels or mutations. This can be explained in a manner where efficacy of a drug is influenced by molecular target and its alterations. One form of such mechanism is that in certain cases, topoisomerase II is targeted by anticancer drugs that prevents under or super-coiling of DNA. The complex that is formed between topoisomerase II and DNA is transient, however, these drugs leads to DNA damage, DNA synthesis inhibition and halting of mitosis. Moreover, cancer cell lines can also develop resistance to this enzyme through mutations that takes place in topoisomerase II gene. Another mechanism that can cause MDR in cancer is through signalling kinases like epidermal growth factor receptor (EGFR) family and downstreaming of signalling proteins like Raf, Ras, Src and MEK (Wu et al. 2014). These kinases are active in some type of cancers promoting uncontrolled cell growth. In such circumstances, over-activation of these kinases is caused by mutations that may also occur due to over-expression of genes. Apart from alterations that occur in drug targets, the resistance occur through alteration in process of signal transduction that mediates activation of drugs.

The mechanism that is most commonly studied in MDR in cancer is drug efflux that involves reduction in drug accumulation through efflux enhancement. ATP-binding cassette (ABC) transporter family proteins are transmembrane proteins that are classified into two domains having highly conserved binding domain for nucleotides and variable transmembrane domain. When a substrate binds to the transmembrane domain, there is hydrolysis of ATP occurring at nucleotide binding site that acts as a driving factor for conformation change pushing the substrate out of the cell. ABC transporters induce efflux considered as normal process; however, it is also a mechanism for MDR in cancer cells. There are three transporters called multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) that are responsible for MDR in cancer (Zahreddine and Borden 2013). These transporters have broad specificity for substrates and as a result, efflux the xenobiotics from the cells. Therefore, the cancer cells are protected from first line chemotherapies inducing MDR.

DNA damage repair also performs a role in developing MDR. Chemotherapies indirectly or directly damage DNA and its response mechanisms that can reverse the damage that is induced by cancer. For example, few anti-cancer drugs cause DNA crosslink that result in apoptosis. On a contrary, resistance to these drugs arises due to homologous recombination and nucleotide excision repair that reverses the effect of this anticancer drug property. Moreover, impairment or dysregulation of DNA damage response (DDR) due to epigenetic silencing or mutations can result in increased resistance and failure to chemotherapy (Gillet and Gottesman 2010).

Cell death inhibition is another mechanism where recombinant forms of TNFs related apoptosis-inducing ligand (TRAIL) induce apoptosis through caspase-8 activation. However, results showed that prolonged use of these drugs causes resistance and they need to be used in combination with other cytotoxic drug so that it kills the cancer cells in vulnerable states (Zahreddine and Borden 2013).

Epithelial-Mesenchymal Transition and Metastasis (EMT) is a process where solid tumors metastatic causing angiogenesis. EMT plays an important role in drug resistance development depending on the metastatic tumor grade defined by EMT degree and level of differentiation. MDR that occur in cancer cells during differentiation and its signaling process are essential for the mechanism of EMT. For example, in colon cancer, there is increased integrin αvβ1 expression that regulates positive transforming growth factor β (TGFβ) expression, EMT expression and acts as survival signal for the cancer cells against anticancer drugs (Housman et al. 2014).

Cancer cell heterogeneity is a mechanism involved in MDR where fraction of cells presents in heterogenous populations possess stem cell properties and drug resistant. Moreover, small fraction of adult stem cells (ASC) also has MDR capabilities. Cancer treatment kills drug sensitive cells and result in drug resistance where cancer cells survive, grow, expand and metastasize. Drugs that may go into circulation and form secondary tumours in the distant organs in the body kill some of these resistant cells. As a result, heterogeneity is witnessed in cancer in both solid tumours and circulation (Zahreddine and Borden 2013).  

Drug repurposing is commonly referred to as therapeutic switching or re-tasking encompasses the application of drugs and compounds that are known, with the aim of treating particular diseases. It has been identified as a promising pharmaceutical strategy that effectively reduces the resources required for development of therapies for certain diseases. The process also amplified the probability of the drug entering the market from phase I, for new indications (Strittmatter 2014). This approach of drug repositioning is found to primarily capitalize on and utilise the fact that a range of abandoned, approved drugs, and other compounds have been already tested in humans. In addition, the detailed information widely available on the formulation, pharmacology, potential toxicity and dose of the drugs help in redevelopment of the drug for use in a different disease or illness. The process is underpinned by the fact that a plethora of molecular pathways has been recognised to play an important role in the onset of several diseases.


The major advantages of repositioning over conventional drug discovery procedures are associated with the significant reduction in the cost and time of development, owing to the fact that safety demonstration of most of these drugs in humans often negates the requirement for conducting phase I clinical trials (Andrews, Fisher and Skinner-Adams 2014). In addition, there exist huge numbers of potential drugs that never reach stages of clinical testing. Moreover, less than 15% of the pharmaceutical compounds that enter the clinical development are able to obtain an approval, majority of them being considered safe. Formulating new drug indications are considered beneficial for patients, both for failed and approved drugs, the safety of which has already been established (Xu and Wang 2013). Drug repurposing approaches span a plethora of disease areas, namely sildenafil, the phosphodiesterase inhibitor, cures coronary artery disease treat cyclooxygenase inhibitor aspirin, erectile dysfunction and gastric motility is cured by erythromycin. In addition, drugs that are said to create adverse effects also merit reconsideration, as is evidenced by an effective reprofiling of thalidomide, the antiemetic for treating multiple myeloma.

While there are, several benefits of drug repositioning, success till date are mostly unanticipated. Large scale, systemic drug re-profiling have not be quite possible, owing to the lack of drug collection by physical means, low drug annotation quality and lack of sufficient readouts related to drug activity, from which a range of drug indications can be easily predicted. Recent studies have provided evidence for gene expression profiling techniques that have enabled drug repurposing discoveries, which includes sirolimus, used for acute lymphocytic leukemia that is glucocorticoid-resistant, topiramate for treating inflammatory bowel disease, and imipramine for the treatment of small cell lung cancer (Bertolini, Sukhatme and Bouche 2015). Quite recently, an assay has also been developed with the use of barcoded cell lines, commonly referred to as PRISM, for cancer therapeutics that enables the quick testing of several drugs against huge cancer cell lines. Approximately 10 drug candidates are required to enter human investigation, with the purpose of producing a fresh molecular entity product. This process generally follows screening of thousands of members of the molecular library that are structurally optimised and tested to determine the animal toxicology effects (Stenvang et al. 2013).

Thus, risks of R&D are greatly reduced upon starting with products that have already been passed through the stages of development. In other words, upon comparison of drug repositioning with use of conventional approaches, the former has been found to have a high success rate (25% versus 10%). Thus, one substantial advantage of the procedure is related to its ability of obtaining ‘method-of-use’ patents designed in a way that promotes the discovery of secondary benefits of the compounds.

Although cancer is, a major health issue on a global basis, limited success obtained by implementation of current therapies have resulted in greater investments for drug development. A decline has also been observed in the average FDA approvals for anti-cancer drugs. The failure to meet the needs of appropriate cancer treatment drugs have increased the interest in drug reposition where already approved drugs, commonly used for other indications, will be used to treat cancer (Gupta et al. 2013). In the context of treating cancer, terminal or rare oncological manifestations are found to afford less restrictions on the safety of the drugs and compounds, owing to the ever increasing demand of novel treatment therapies. In addition, cancer is also manifested in the form of a multistage disease, with interventions targeting different phases of carcinoma initiation, rapid growth, metastasis and recurrence.

These features provide the indication that drug repurposing that is focused on cancer treatment would have mutual benefits for both the pharmaceutical companies and the patients alike. Studying the ability of a drug to bring about changes in the expression profile of cancer cells have also allowed drawing inferences about their mechanism-of-action (Xu et al. 2014). The approach has eventually resulted in the discovery of major antitumor properties of trifluoperazine, which was previously approved in the form of an antidepressant for treating schizophrenia (Koch et al. 2014).

Some of the conventional use of the repurposed drug anisomycin is associated with inhibition of protein and DNA synthesis. It has also gained potential as a psychiatric drug and has been identified beneficial for selective removal of memories, brought about by injection of the drug into the hippocampus. Anisomycin also seems useful during transition of normal to fibrotic lungs, both during stages 1 and 2 of idiopathic pulmonary fibrosis, due to its role in inhibiting ER stress induction (Karatzas et al. 2017). Owing to the fact that repurposing is a major alternative to conventional use of drugs, anisomycin has also been subjected to re-profiling in several studies (Monaghan et al. 2014).

The antibiotic anisomycin has been recognised as one of the most effective compounds, during secondary screening of compounds. Anisomycin has been found highly effective against specific subsets of TNBC cell lines, in addition to some in vitro cell lines of prostate cancer. The drug has also shown its benefits in inducing ribotoxic stress in MDA-MB-468 TNBC cell line, evidenced by JNK activation (Cruickshank 2016). This activation generally occurs by inducing caspase-3 processing and caspase-3 like activity. This antibiotic anisomycin has been found to induce death of the tumor cells, along with display of metastatic activity, when coupled with apoptosis (Boyer et al. 2018). Thus, even low doses of anisomycin have the ability of inhibiting protein synthesis in cases of melanoma.

Cell death refers to the event that encompasses death of a biological cell that subsequently ceases to conduct all its functions (McIlwain et al. 2013). Cell death might occur due to natural process of death of old and damaged cells that are replaced by new ones, or might also result due to localised injuries, diseases or death of the organism.

This refers to the form of programmed cell death occurring in multicellular organisms where a set of biochemical events bring about changes in the cell morphology and its subsequent death. Some of the most characteristic changes that occur in apoptosis include blebbing, nuclear fragmentation, cell shrinkage, chromosomal DNA fragmentation and chromatin condensation. Upon comparison with traumatic cell death or necrosis, apoptosis has been identified to be highly controlled and regulated that confers several advantages during the lifecycle of an organism. The intrinsic pathway of apoptosis involves an event where the cell kills itself due to sense of stress. On the other hand, the extrinsic pathway is followed when the cells kills itself due to reception of signals from adjacent cells. Apoptotic pathways are induced by activation of caspases, a class of protease that are responsible for degradation of proteins (Mukhopadhyay et al. 2014). Excess apoptosis most often leads to atrophy or reabsorption and breakdown of the cells and tissues.

However, less apoptosis has been found responsible for uncontrolled cell proliferation, commonly referred to as cancer. Disruption in the apoptotic pathway results in increase in the progeny of cells that have faulty machinery, which in turn increases the likelihood of the cells becoming cancerous. Damage of DNA due to biochemical factors leads to the accumulation of tumor suppressor protein p53 (Motawi et al. 2014). Induced transcription of p53 results in its increase and cancer cell-apoptosis enhancement. Disruption in p53 regulation is responsible for apoptosis in impairment and possible tumor formation.

This is a programmed pattern of inflammatory cell death or necrosis and is associated with cell death that occurs due to damage of the cells or pathogen infiltration. This is generally defined as a form of defence mechanism, initiated by viruses. This facilitates undergoing of cellular suicide in a manner that is independent of the caspase enzymes. Necroptosis has also been identified as an integral component of cvarious inflammatory diseases such as, pancreatitis, myocardial infarction and Chron’s disease (Kaczmarek, Vandenabeele and Krysko 2013). TNFα, the cell signalling protein is produced during viral infection that results in stimulation of the TNFR1 receptor. RIPK1 is signalled by TRADD, the TNFR-associated death protein, which sends signal to the RIPK3, to form the necrosome. Necroptosis is generally characterised by necrotic cell death morphology that is controlled by RIP3, RIP1, and kinase domain-like proteins of mixed lineage.


In addition, the physiological role of necroptosis is associated with serving as a "fail-safe" cell death form for specific cells failing to undergo apoptosis, at the time of disease defence and embryonic development. Cells that undergo necroptosis often rupture and leak the contents in intercellular space (Pasparakis and Vandenabeele 2015). Necroptosis has also been associated with initiation of cancer and its progression. Elevation in necroptosis often increases the risks of metastasis and proliferation of the cells by generating reactive oxygen species and suppressing immune response. Recent studies have established necroptosis based cell therapies as essential antitumor treatment strategies.

This refers to an inflamed pattern of programmed cell death that is found to occur more upon acquiring infections caused by intracellular pathogens. Pyroptosis is most likely to become a part of antimicrobial response in the body. The process involves recognition of danger signals that trigger the release of cytokines, followed by swelling, bursting and death of the cells. These cytokines are found to play a crucial role in attracting other immune cells that help in fighting infections and contribute to tissue inflammation. Pyroptosis also promotes clearance of different viral and bacterial infections that is facilitated by the removal of intracellular replication niches, thereby enhancing the defensive responses of the host (Doitsh et al. 2014). However, in case of pathogenic chronic diseases, these inflammatory response fail to eliminate or eradicate primary stimuli, as is normally found in most cases associated with injury or infection. This ensues a chronic and severe form of inflammation that is found to potentially result in tissue damage.

Pyroptosis initiation in infected macrophage is brought about by flagellin component recognition of Shigella and Salmonella species with the help of NOD-like receptors that recognise antigen present within cells. Caspase-1 function is also crucial in the process of pyroptosis (Case et al. 2013). The enzyme gets activated in the process with the help of major supramolecular complexes called pyroptosome, composed of ASC protein dimers. In other words, the process is a pathway that is linked to cell death, mediated by caspase-1 activation. Failure of the cells to respond to particular stimulus and die subsequently results in organ dysfunction and abortive embryogenesis, all of which contribute to cancer initiation.

This kind of programmed cell death is primarily characterised by lipid peroxidase accumulation and is dependent on iron. The process is biochemically and genetically distinct from other cell death forms. Failure of the antioxidant defences that are glutathione dependent initiate the process of ferroptosis and remove the check on lipid peroxidation, thereby resulting in cell death. Iron chelators and lipophilic antioxidants (Jiang et al. 2015) can generally prevent Ferroptotic cell death. The process is also initiated by direct loss of GPX4 activity that is mediated by inhibition of Xc- system. This kind of cell death is found to occur during events that involve uptake of electrons by the free radical molecules from some lipid molecule. This facilitates the degradation or degeneration of the lipid molecule. Oxidation of the lipid molecules result in loss of electrons to free radical molecules, thereby acting as a trigger for the degradation.

Activation of ferroptosis has been identified to play an essential role that regulates the growth of tumor and carcinoma cells in the human body. Thus, ferroptosis can significantly contribute to the field of research and medicine in devising cancer treatments that involve induction of this kind of cell death in the human body (Angeli et al. 2014). Ferroptosis induced by small molecules such as, erastin, has been found to act as strong inhibitors of tumor growth and subsequently enhance sensitivity of certain chemotherapeutic drugs namely cisplatin, temozolomide and adriamycin, mostly in conditions that are associated with drug resistance.

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