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Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue
Dissertation(MSc)--University of Pretoria, 2016.
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| Format: | Thesis |
| Language: | English |
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2026
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| _version_ | 1867613651846823936 |
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| access_status_str | Open Access |
| author2 | Theron, A. |
| author_browse | Theron, A. |
| author_facet | Theron, A. |
| collection | Thesis |
| description | Dissertation(MSc)--University of Pretoria, 2016. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/110104 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:39:32.610Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/110104 Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue Theron, A. elsa07.nolte@gmail.com Joubert, Annie M. Lakier, R. Nolte, Elsie Magdalena Cancer radiation therapy 2-methoxyestradiol ESE-15-ol radiosensitization reactive oxygen species Bcl-2 HDAC 1 and -2 p53 apoptosis autophagy Dissertation(MSc)--University of Pretoria, 2016. 2-Methoxyoestradiol (2-ME) is known to suppress tumour growth and inhibit angiogenesis of several tumours cell lines. Drug-resistant cancer cells were successfully treated with 2-ME via the induction of the intrinsic- and extrinsic apoptotic pathways. Several in vitro- and in vivo studies have shown that 2-ME is a spindle poison and by binding to the colchicine site, causes the formation of abnormal mitotic spindles, as well as mitotic accumulation. 2-ME has also been reported to radiosensitize prostate cancer cells in an in vitro- and in vivo experimental setting. 2-ME is rapidly metabolised resulting in a low bioavailability. Thus, sulphamoylated 2-ME analogues were in silicodesigned in order to overcome these pharmacokinetic constraints. These compounds have an increased half-life and a higher bioavailability compared to the parent compound. One of these analogues, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen17-ol (ESE-15-ol), was used in this study. The aim of this in vitro study was to determine whether low dose of ESE-15-ol pre-exposure increases the sensitivity of breast (MCF7)- and lung (A549) cancer cells to _-radiation. Cytotoxicity studies on A549- and MCF-7 cell lines were completed with 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining. Morphological studies included light- and transmission electron microscopy. Clonogenic studies were done by seeding cells at a density of 100 cells for the DMSO control, 400 cells for ESE15-ol only control and 1000 cells for the radiation- and combination conditions. Termination followed 10 days after radiation by crystal violet staining. Flow cytometry in combination with annexin V-FITC and propidium iodide was used for apoptosis detection. To determine reactive oxygen species production (superoxide) within the cells flow cytometry was employed. Effects on epigenetics were determined by flow cytometry employing histone deacetylase 1 and -2. Differences in signalling pathways were determined by flow cytometry by measurement of anti-Bcl-2 antibody conjugated to AlexaFluor® 488. Autophagy (LC3-II) and p53 expression were quantified by western blot analysis. iii MCF-7- and A549 cells were exposed to 56nM and 81nM of ESE-15-ol, respectively at which apoptosis is first detectable, for 24 hours followed by _-radiation (6 Gy). After 48 hours, cell morphology results showed decreased cell density, apoptotic bodies and cellular protrusions when compared to the negative control. Flow cytometric analysis revealed an increased number of cells in apoptosis (Annexin V-FITC) and in the sub-G1 phase (cell cycle analysis) in presensitized cells. Clonogenic studies revealed a decrease in colony formation in presensitized A549- and MCF-7 cells when compared to the individual treatment conditions. Flow cytometry employing hydroethidine revealed increased superoxide production in presensitized cells. HDAC1- and -2 expression were significantly increased in presensitized A549- and MCF-7 cells when compared to the individual treatment conditions. Additionally, p53 expression was significantly increased in A549- and MCF-7 cells exposed to the compound prior to radiation. No LC3-II expression was observed in any treated samples. Pre-treatment of MCF-7- and A549 cells with ESE-15-ol for 24 hours sensitized cells to _-radiation and induced programmed cell death via apoptosis more so than ESE-15-olor radiation-exposure alone. Future studies will investigate the effect of ESE-15-ol-preexposure on DNA damage and DNA repair mechanisms induced by _-radiation. Physiology MSc 2026-05-15T17:26:18Z 2026-05-15T17:26:18Z 16/02/03 2016 Dissertation http://hdl.handle.net/2263/110104 en |
| spellingShingle | Cancer radiation therapy 2-methoxyestradiol ESE-15-ol radiosensitization reactive oxygen species Bcl-2 HDAC 1 and -2 p53 apoptosis autophagy Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title | Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title_full | Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title_fullStr | Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title_full_unstemmed | Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title_short | Potential radiosensitization of breast- and lung cancer cells by a novel antimitotic oestrogen analogue |
| title_sort | potential radiosensitization of breast and lung cancer cells by a novel antimitotic oestrogen analogue |
| topic | Cancer radiation therapy 2-methoxyestradiol ESE-15-ol radiosensitization reactive oxygen species Bcl-2 HDAC 1 and -2 p53 apoptosis autophagy |
| url | http://hdl.handle.net/2263/110104 |