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Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines
Thesis (PhD (Radiography))--University of Pretoria, 2024.
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University of Pretoria
2025
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| _version_ | 1867613642242916352 |
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| access_status_str | Open Access |
| author2 | Joubert, Anna Margaretha |
| author_browse | Joubert, Anna Margaretha |
| author_facet | Joubert, Anna Margaretha |
| collection | Thesis |
| dc_rights_str_mv | © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Radiography))--University of Pretoria, 2024. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/100727 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:39:23.523Z |
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| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/100727 Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines Joubert, Anna Margaretha seanee@cput.ac.za Nair, Shankari Vandevoorde, Charlot Seane, Elsie Neo UCTD Sustainable Development Goals (SDGs) Histone deacetylase inhibitor Radiosensitising efficacy Photon therapy Proton therapy Metastasis and relative biological effectiveness Thesis (PhD (Radiography))--University of Pretoria, 2024. Introduction: Photon-based radiation therapy remains to be an important treatment modality in the management of breast cancers. However, proton therapy has attracted a lot of interest due to the ability to reduce dose to healthy tissues. It is rapidly evolving as a radiation therapy tool for women with left-sided breast cancer in order to limit unnecessary dose to the heart and reduce the risk of long-term cardiac morbidity. In addition to the evolution in radiation therapy modalities, increasing evidence shows that histone deacetylase inhibitors (HDACi) are able to sensitise cancer cells to ionising radiation with little effect on healthy cells. Studies on radiosensitising capabilities of HDACi in combination with proton irradiation remain limited. To date, the published manuscripts presented in this thesis were the first to be published on radiosensitising capabilities of HDACi in combination with proton therapy in breast cell lines. Aim and hypothesis: The study aimed to compare in vitro radiosensitising capacities of two different HDACi, suberoylanilide hydroxamic acid (SAHA) and CUDC-101, to photon and proton irradiation in multiple breast cell lines. CUDC-101 is an inhibitor of histone deacetylases (HDACs), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and was therefore expected to be a more effective radiosensitiser than SAHA. Research design: The study followed a factorial experimental design with three main effects (HDACi, cell types, radiation types) with three repeats and 180 observations. Methods: MCF-7, MCF-10A and MDA-MB-231 human breast cell lines were utilised to conduct cell proliferation, clonogenic survival, gamma-Histone subtype H2A isoform X (γ-H2AX), cell migration, apoptosis and cell cycle analysis assays. Cells were pre-treated with HDACi and each sample irradiated at room temperature with varying doses of 184 MeV proton irradiation or 250Kvp X-rays. Data analysis was conducted using Graphpad Prism software. For statistical analysis, unpaired Student t-tests were used to test for significance. Testing was done at the 0.05 level of significance. Significance of the study: The study contributes new knowledge on HDACi-mediated sensitisation of breast cell lines to proton irradiation. The results highlighted the role of CUDC-101 as a potent radiosensitizer and a promising strategy to mitigate breast cancer metastasis. The results also add to the ongoing efforts to clarify the mechanisms that underlie the radiosensitising effects of HDACi particularly to proton irradiations. Results: Both HDACi, SAHA and CUDC-101 are able to enhance the radiation-induced cytotoxicity in the MCF-7 and MDA-MB-231 breast cancer cell lines when combined with either X-rays or protons. In the triple negative MDA-MB-231 cell line, increased DNA DSB induction and retention following treatment with CUDC-101 or SAHA monotherapy and in combination treatments with 2Gy protons or X-rays. An unexpected finding in the study was the increase in migration and invasion after SAHA treatment in the MCF-7 cell line, whereas both SAHA and CUDC-101 reduced migration and invasion in the triple negative MDA-MB-231 cells. Department of Higher Education and Training vNRF iThemba Laboratories Radiography PhD (Radiography) Unrestricted Faculty of Health Sciences SDG-03: Good health and well-being 2025-02-11T18:21:55Z 2025-02-11T18:21:55Z 2025-04 2024-11 Thesis * A2025 http://hdl.handle.net/2263/100727 https://doi.org/10.25403/UPresearchdata.28385372.v1 https://doi.org/10.25403/UPresearchdata.28385372 en © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD Sustainable Development Goals (SDGs) Histone deacetylase inhibitor Radiosensitising efficacy Photon therapy Proton therapy Metastasis and relative biological effectiveness Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title | Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title_full | Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title_fullStr | Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title_full_unstemmed | Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title_short | Radiosensitising efficacy of histone deacetylase inhibitors CUDC-101 and SAHA in breast cell lines |
| title_sort | radiosensitising efficacy of histone deacetylase inhibitors cudc 101 and saha in breast cell lines |
| topic | UCTD Sustainable Development Goals (SDGs) Histone deacetylase inhibitor Radiosensitising efficacy Photon therapy Proton therapy Metastasis and relative biological effectiveness |
| url | http://hdl.handle.net/2263/100727 https://doi.org/10.25403/UPresearchdata.28385372.v1 https://doi.org/10.25403/UPresearchdata.28385372 |