The programmed cell death that occurs in multicellular organisms is what is referred to as apoptosis (Kumar 1998). It involves a number of biochemical reactions that result to a characteristic morphology of the cell and eventually cell death. These morphological changes that occur in the cell are changes in the cell membrane asymmetry and attachment, shrinking of the cell, fragmentation of the nucleus, fragmentation of the chromosomal DNA and condensation of the chromatin (Potten & Wilson 2004).

Apoptosis is different from necrosis in that necrosis is the traumatic death of the cell that occurs as a result of acute cellular injury. Sometimes apoptosis is referred to as the committing suicide of a cell (Kuchino & Muller 1996). There are three main mechanisms by which a cell can ‘commit suicide’ through apoptosis; the first mechanism is through a signal generated by the cell to self destroy through the intrinsic or the mitochondrial pathway. The outer membranes of a healthy cell display a protein called Bcl-2 which inhibits apoptosis.

The damage of a cell internally causes the cell to produce a related protein called Bax that migrates to the surface of the mitochondrion to inhibit the protective effects of Bcl-2. It also inserts itself on the outer mitochondrion membrane causing cytochrome c to leak out (Tomei & Cope 1991). This cytochrome c then binds to Apaf-1 an apoptotic protease that activates factor-1 to form complexes called apoptosomes that activates caspase-9. This activates caspases that causes cascades of proteolytic activity which leads to digestion of the structural proteins and degradation of the chromosomal DNA (Kaufmann 1997).

The second mechanism involves the cell being triggered to self kill by external signals or apoptosis through what is called the extrinsic or the death receptor pathway. The cell receptors that are involved in this mechanism are the Fas and the TNF receptors that bind complementary death activators to transmit the signals for cell death to the cytoplasm. The cascades of cell death are initiated by the activation of caspase 8 (Rustin, Newlands, Begent, Dent & Bagshawe 1989). The other mechanism involves the apoptosis inducing factor (AIF).

This mechanism unlike the other two does not involve activation of any cascade pathway. This AIF is a protein found in the intermembrane space of the mitochondria which when released migrates to the nucleus and binds to the DNA triggering the destruction of the DNA in the process and ultimately causing cell death. Proteasome inhibitors (MG132) This is a specific, reversible, cell permeable and potent proteasome inhibitor. It is also referred to as N-(benzyloxycarbonyl) leucinylleucinylleucinyl and has a molecular formula of C26H41N3O5 with a molecular weight of 475.

62g/ mol1. This inhibitor reduces the degradation of the ubiquitin conjugated proteins in the cells by the 26S complex without affecting the cells ATpase or isopeptidase activities. It activates the c-Jun N-terminal protein kinases a process that initiates apoptosis. The proteasome inhibitor MG132 up regulates the expression of Apo2L/TRAIL death receptor 5 in cells with sufficient levels of Bax and also in those cells with deficiency in HCT116 (Aghajanian, Soignet, Dizon, Pien, Adams, Elliott, Sabbatini, Miller, Hensley, Pezzulli 2002).

This inhibitor cooperates with the death receptor Apo2L/TRAIL to induce apoptosis in both the cells proficient in Bax and cells deficient in Bax and HCT116 that had been coupled with caspases-8 and caspases-3 activation and cleavage by Bid (Adams, Palombella, Sausville, Johnson, Destree, Lazarus, Maas, Pien, Prakash & Elliott 1999). Both of these proteins also induce cytochrome c and Smac release by the mitochondria into the cell cytosol an occurrence that activates the caspase-9 reactions in the Bax proficient cells but these events are significantly decreased in Bax deficient cells.

As little as 0. 5 micro molecules of MG132 can cause a significant level of apoptosis in both cells. It can cause DNA damage, cleavage of the poly ADP ribose polymerase and also the activation of caspases 7, 9 and 3 and makes the mitochondria release Smac/DIABLO and cytochrome c. the activation of the caspase system is the underlying mechanism of apoptosis induced by the MG132 inhibitor (An, Sun, Fisher, Rettig 2004). Mcl-1 which is an inhibitor of apoptosis protein is a major inhibitor of apoptosis induced by MG132 inhibitor in the MPM cells (malignant Pleural mesothelioma).

Sub apoptotic doses of MG132 inhibit the invasion of the MPM cell lines by reducing the Rac1 activity. This shows that MG132 has proapoptotic and anti invasion properties in the human MPM cells (Adams 2002b). Literature Review The purpose of this study is to establish the mechanism of MG132 proteasome inhibitor in inducing apoptosis in cells both by itself or when assisted by other mechanisms. The study is also going to assess the structure of the protein and look at the functions of the MG132 inhibitor in leukemia cell lines and in solid tumors and the role it plays in these cancers.

This literature review was conducted using a variety of sources the main one being the online sources. The scholar google search engine and the proquest such engines were particularly helpful. These search engines provided an extensive amount of information that is based on research. MG132 is a major factor in the process of apoptosis. Relevant Theoretical literature A wide variety of literature is available on induction of apoptosis by MG132. A search through the EBSCO search engine availed a lot of articles that have been published in regards to this topic.

Because all of them can not be used in the study a few were chosen that pertain the topic to be researched. A recent article published in 2008 suggested that the mitochondrial caspase activation cascades were the underlying mechanisms of the induction of apoptosis of by the MG132 protein (Adams 2002a). The article also mentions that the MG132 demonstrated proapoptotic and anti invasion properties in MPM cells. The article mentioned that an increase in the G0/G1 cells after treatment with or exposure to MG132 indicates that apoptosis has been induced in the cells by the protein (Yuan, Chapman & Reynolds 2008).

Another article published in 2009 showed that treatment of PEL (primary effusion Lymphoma) with Mg132 suppresses the proliferation of cells and also indicated that t5he treatment induces apoptosis in several cell lines of PEF (Hussain, Ahmed, Ahmed, Al-Thari, Khan, Razack, Platanias, Al-Kuraya & Uddin 2009). This treatment was showed to involve the down regulation of the S-phase kinase proteins and the accumulation of p27Kip1 (Tenev, Marani, McNeish, Lemoine 2001).

The article illustrated that the treatment with MG132 caused conformational changes that led to the loss of the mitochondrial membranes potential and the release of cytochrome c into the cytosol. These events led to the activation of the caspase proteins and therefore apoptosis. Another article published in 2004 showed the molecular mechanisms of apoptosis and the arrest of G (2)/M in leukemia cell lines HL-60 were induced by the proteasome inhibitor MG132. The articles mentions that the MG132 inhibitor induced apoptosis in the HL-60 cells after treatment for 24 hours.

The article concludes that proteasome inhibitor Mg132 can induce the arrest of the G2/ M before the appearance of apoptosis in the HL-60 cells (Sun, Qian, Meng, Song , Zhang, Mei, Dong & Sun 2004). Another article was published in 2005 that showed that treatment of LNCaP cells with higher doses of MG132 of approximately 0. 5 micro molecules caused apoptosis. The article shows that further increment of the inhibitor resulted to a curvilinear response leading to a 13 fold increase in apoptosis.

Combining the treatment with MG132 with lactacystin treatment is shown to yield a higher increment in apoptosis (Wente, Eibl, Reber, Furies, Buchler & Hines 2005). Relevant Research Research on the induction of apoptosis by the MG132 inhibitor is numerous and just like in the relevant theoretical literature just a few of these researches are going to be looked at in this study. A research was conducted in 2005 to investigate whether the cell permeable proteasome inhibitor the MG132 could reduce growth of human pancreatic cancer cell line by the induction of apoptosis (Shirley, Kaddour-Djebbar, Patel, Lakshmikanthan, Lewis & Kumar 2005).

The researchers analyzed the effects of the inhibitor on the growth of the pancreatic cancer cell line BxPC-3 by cell count and MIIT assay. The study found out that MG132 had decreased the cell growth of the pancreatic cancer line BxPC-3 in a manner that dependent on time and dose an effect that was mediated by apoptosis (Hendrix, Seftor, Meltzer 2001). Another research was launched in 2003 to study the effects exerted on the human osteosarcoma Saos-2 cells by the proteasome inhibitor MG132. The study found out that MG132 strongly reduced the viability of the Saos-2 cells in a manner that dependent on time and dose.

After 48 hours of treatment the viability of the cells had decreased by 50%. The study found out that these cells that had lost viability had a round shape and had detached from the substrate (Lauricella, D’Anneo, Giuliano, Calvaruso, Emmanuelle, Ventoand & Tesoriere 2003). The research demonstrated that the cause of cytotoxicity caused by MG132 was because of the induction of apoptosis. The study also showed that MG132 also led to increase in the levels of the reactive oxygen species which was anticipation for the MG132 triggered apoptosis.

Another research conducted in 2007 showed the ubiquitin proteasome pathway as a promising approach in the treatment of cancer. The study showed that proteasome inhibitors like MG132 can induce the accumulation of intracellular polyubiquitinated proteins and extensive vacuolization in the cells due to ER stress (Ding, Ni & Yin, 2007). The transcriptional inhibitors then suppressed the MG132 induced polyubiquitinated protein accumulation which in turn inhibited the ER stress induced by MG132, the cellular vacuolization and cell death (Orlowski, Stinchcombe, Mitchell, Shea, Baldwin, Stahl, Adams, Esseltine, Elliott, Pien 2002).

This study therefore concluded that the proteasome inhibitors like MG132 can be very useful chemotherapeutic agents in solid tumors especially because they can induce non apoptotic cell death and also apoptotic cell death which can help in overcoming resistance caused by a compromised apoptotic mechanism. Recent researches indicate that the nuclear factor-KB (NF-KB) activation is one of the key factors in apoptosis and that it can be inhibited or prevented by the abrogation of the IkB alpha protein degradation by the proteasome inhibition.

A research was conducted to investigate the effects of MG132 and some other proteasome inhibitors on apoptosis using a human leukemia cell lineU937 and leukemia blasts freshly isolated from patients of acute leukemia (Watanabe, Kubota, Hamahata, Lin & Usami 2000). The study established that pre-treating the U937 cells with MG132 inhibited etoposide induced apoptosis and caspase3 activation; it also inhibited the activation of NF-KB and the degradation of IkB alpha (Nawrocki, Bruns, Harbison, Bold, Gotsch, Abbruzzese, Elliott, Adams & McConkey 2002).

The study therefore concluded that the role played by NF-KB in apoptosis induced by etoposide in the leukemia cell line is different fro the role it plays in the leukemia blasts that have been freshly isolated because MG132 caused apoptosis in the leukemia blasts at the concentrations that the study used (Jui-yu, Mackenzie, Cook, Scott, Pinchot, Muthusamy & Herbert 2009). Implications for Practice These studies show that the proteasome inhibitors and especially the MG132 inhibitor are important in clinical practices. Much research and studies have been carried out to show that MG132 can be used in the oncological practice effectively.

Most studies have shown that MG132 inhibits the growth of cancer cells and the neuroendocrine phenotype. This inhibitor warrants more clinical investigation and testing as a possible strategy for therapy for intractable carcinoid diseases. Some studies however specify that only specific concentrations of the inhibitor can cause significant apoptosis in the cancer cells. More research therefore should be done to establish the specific concentrations needed to completely kill the tumor cells in cancer patients. Implications for inquiry

Most of the researches that have been published have not shown whether this inhibitor can be effective in killing cells from all kinds of tumors. It is also important that the research be availed to be proved that they work because no research has mentioned if there has been any successful trials in patients in treating cancer (Williams, Pettaway, Song, Papandreou, Logothetis, & McConkey 2003). More research still has to be done to confirm if the therapy of cancer using the proteasome inhibitors is effective by itself or when combined with other forms of therapy.

These researches also have to indicate or conduct further studies on whether this kind of therapy on cancer patients can completely eliminate the cancer. Conclusion All the studies reviewed here seem to have used the same methodology of getting results that is by imposing an intervention or treatment on one group of cells and then the researcher observes the effects of the treatment on the subject cells and compares the results to those obtained from a controlled group of cells.

Some of these studies take more than a year to be completed while others just take months or weeks. In the following study the methodology will be somewhat the same as the studies that have been looked at above. References Adams, J 2002a, ‘Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer’, Curr Opin Chem Biol, vol. 6, pp. 493–500. Adams, J 2002b, ‘Proteasome inhibitors as new anticancer drugs’, Curr Opin Oncol, vol.

14, pp. 628–634. Adams, J, Palombella, VJ, Sausville, EA, Johnson, J, Destree, A, Lazarus, DD, Maas, J, Pien, CS, Prakash, S & Elliott, PJ 1999, ‘Proteasome inhibitors: a novel class of potent and effective antitumor agents’, Cancer Res, vol. 59, pp. 2615–2622. An, J, Sun, Y, Fisher, M, Rettig, MB 2004, ‘Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent’, Mol Cancer Ther, vol. 3, pp. 727–736.

Aghajanian, C, Soignet, S, Dizon, DS, Pien, CS, Adams, J, Elliott, PJ, Sabbatini, P, Miller, V, Hensley, ML, Pezzulli, S, et al 2002, ‘A Phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies’, Clin Cancer Res, vol. 8, pp. 2505–2511 Ding, XZ, Ni, HM & Yin, XM 2007, ‘Absence of Bax switched MG132-induced apoptosis to non-apoptotic cell death that could be suppressed by transcriptional or translational inhibition’, Apoptosis, vol. 12, no. 12, pp. 2233- 2244.

Hendrix, MJ, Seftor, EA, Meltzer, PS, et al 2001, ‘Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry’, Proc Natl Acad Sci U S A, vol. 98, pp. 8018–8023. Hussain, AR, Ahmed, M, Ahmed, SO, Al-Thari, S, Khan, AS, Razack, S, Platanias, LC Al-Kuraya, KS & Uddin, S 2009, ‘ Proteasome inhibitor MG-132 mediated expression of p27Kip1 via S-phase kinase protein 2 degradation induces cell cycle coupled apoptosis in primary effusion lymphoma cells’, vol.

50, no. 7, pp. 1204- 1213. Jui-yu, C, Mackenzie, R, Cook, BA, Scott, N, Pinchot, MD, Muthusamy, & Herbert, CM, 2009, ‘MG-132 Inhibits Carcinoid Growth and Alters the Neuroendocrine Phenotype’, doi:10. 1016/j. jss. 2009. 05. 032. Kaufmann, SH 1997, Apoptosis: pharmacological implications and therapeutic opportunities, Academic Press, London. Kuchino, Y & Muller, WEG 1996, Apoptosis, Springer, New Mexico. Kumar, S 1998, mechanisms and role in disease, Springer, New Mexico.

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