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The cytotoxic effect and molecular targets of ezetimibe in A549 lung cancer cells

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dc.contributor.advisor Ntwasa, M.
dc.contributor.advisor Sooklal, S. A. Munnik, Chamone 2023-09-19T08:40:49Z 2023-09-19T08:40:49Z 2023
dc.description.abstract The p53 gene is a well-known tumour suppressor gene, shown to be dysfunctional in more than 50% of human malignancies. The cellular significance of this oncogene is evident in a series of diverse cellular antiproliferation properties owing to specified cell-cycle checkpoint arrest, cellular senescence, and apoptosis. The multifunctionality of p53 indicates the importance of this protein while also hinting at the diverse regulatory mechanisms required for function and regulation. Since most tumours display dysfunction of p53, considerable efforts are made in the development of cancer therapies exploiting the functions and mutations of p53. MDM2 is a known primary negative regulator of p53. The tight control exhibited by MDM2 on p53 suggests that inhibiting MDM2 could translate to anti-cancerous effects. In silico methods identified ezetimibe (brand-named Zetia) as a potential anti-cancer drug. The computational model revealed high-affinity binding between ezetimibe and the MDM2 hydrophobic cleft of the MDM2 p53-binding site. The observed structure indicates inhibition of p53 binding when MDM2 is bound to ezetimibe, thus preventing the formation of MDM2-p53 complexes. The reduced downregulation of p53 could have immense oncological potential. This study aims to investigate the cytotoxic effect of ezetimibe on A549 lung cancer cells for its potential use as an anti-cancer agent. The safety and efficacy of the drug were monitored on mammalian cells by MTT assay. The analysis of molecular underpinnings of cellular changes caused by ezetimibe was determined with the use of Flow Cytometry, to characterise apoptosis and cell cycle analysis. Moreover, molecular targets of ezetimibe were evaluated using the Drug Affinity Responsive Target Stability (DARTS) method. It should be noted that this study did not investigate the molecular underpinnings of the identified molecular targets. The integrated investigation of the molecular targets is assigned for future studies. This study, therefore, aimed to validate the use of ezetimibe as a viable cancer treatment. The results revealed that ezetimibe is toxic to the A549 cells and not toxic to normal cells and MCF-7 cells at the same concentrations. The cellular changes caused by ezetimibe in apoptosis and cell cycle analysis were consistent with p53 activity. While ezetimibe induced cellular changes in A549 cells, the effect was limited. Finally, the molecular targets of ezetimibe provided numerous proteins with potential therapeutic capacity. While the identified proteins revealed an agglomeration of functions, future pathway analysis is required. This study demonstrated the efficacy of ezetimibe as an anti-cancer agent for A549 human lung cancer cells. en
dc.format.extent 1 online resource (i, 75 leaves) : illustrations (chiefly color), color graphs
dc.language.iso en en
dc.subject.ddc 616.99424
dc.subject.lcsh Lungs -- Cancer -- Treatment en
dc.subject.lcsh Cell-mediated cytotoxicity en
dc.subject.other UCTD
dc.title The cytotoxic effect and molecular targets of ezetimibe in A549 lung cancer cells en
dc.type Dissertation en
dc.description.department Chemistry en M. Sc. (Biochemistry)

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