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Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells
Thesis (PhD (Human Physiology))--University of Pretoria, 2019.
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University of Pretoria
2019
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| _version_ | 1867613662785568768 |
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| access_status_str | Open Access |
| author2 | Mercier, Anne Elisabeth |
| author_browse | Mercier, Anne Elisabeth |
| author_facet | Mercier, Anne Elisabeth |
| collection | Thesis |
| dc_rights_str_mv | © 2019 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 (Human Physiology))--University of Pretoria, 2019. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/68925 |
| institution | University of Pretoria (South Africa) |
| last_indexed | 2026-06-10T12:39:43.129Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| 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:2263/68925 Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells Mercier, Anne Elisabeth Lafanechère, Laurence elsa07.nolte@gmail.com Joubert, Anna Margaretha Lakier, Roy Nolte, Elsie Magdalena UCTD Sustainable Development Goals (SDGs) Human Physiology Cell Biology Cancer Mitochondria Radiosensitization Radiation therapy Thesis (PhD (Human Physiology))--University of Pretoria, 2019. Microtubule targeting agents are effective anti-cancer drugs. Their use as part of a combined treatment modality with ionising radiation is also a promising strategy. However, the emergence of chemical and radiation resistance requires searching for alternative treatments. Our laboratories have recently described several drugs that directly or indirectly target the cellular microtubules. 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16), an analogue of 2-methoxyestradiol, is a microtubule targeting agent that binds to microtubules causing the formation of abnormal mitotic spindles. 9-Benzoyloxy-5,11-dimethyl-2H,6H-pyrido[4,3-b]carbazol-1-one (LimPyr1) is a novel inhibitor of LIM kinases that indirectly induces microtubule stabilization. As microtubule-targeting drugs, both agents, ESE-16 and LimPyr1, induce mitotic defects. We thus hypothesized that they could sensitize cells to radiation as the G2/M phase is the most radiosensitive phase of the cell cycle. The aim of this PhD project was to test that hypothesis and, more specifically, to investigate whether low-doses of ESE-16 and LimPyr1 could increase apoptosis and delay nuclear repair induced by radiation in breast cancer cells in vitro. Breast cancer cell lines namely MCF-7-, MDA-MB-231- and BT-20 cells, were exposed to ESE-16 and LimPyr1 for 24-hours prior to 8 Gy radiation. The effects of these combination therapies were compared to those obtained from cells exposed to the compounds alone or only to radiation. The activation of the survival and intrinsic apoptotic pathways were investigated. Results revealed altered survival and death signaling in cells exposed to the individual treatments. The combination treatments decreased cell survival while apoptotic signaling was increased, resulting in increased cell death. Furthermore, the combination treatments significantly increased the presence of micronuclei in BT-20 cells, indicating an increase in deoxyribonucleic acid (DNA) damage. MCF-7- and MDA-MB-231 cells displayed similar micronuclei formation when exposed to the combination treatments or radiation only. Phosphorylation of H2AX (γH2AX) (normally increased upon DNA damage) and Ku70 expression (required for DNA repair) were decreased in pre-treated breast cancer cells 2 hours after irradiation compared to cells exposed to radiation only. The expression of γH2AX and Ku70, however, were significantly increased 24 hours after irradiation in the pre-treated cells. LimPyr1 decreased radiation resistance development from dose fractionation by increasing the permeability of the mitochondrial membrane. An increase in the generation of reactive oxygen species (ROS) was not observed in ESE-16 pre-treated cells exposed to fractionated radiotherapy. We also observed pro-apoptotic signaling between cells exposed to radiation and non-exposed cells via the radiation-induced bystander effect. In conclusion, the anti-mitotic effect of ESE-16 and LimPyr1 renders the chromosomes more exposed to radiation damage as assessed by the increased occurrence of micronuclei. Moreover, both compounds decreased the signaling and trafficking of DNA damage and repair proteins. Additionally, LimPyr1 prevented the development of radiation resistance in cells exposed to fractionated radiation doses. Future studies will aim to elucidate the molecular mechanisms responsible for ESE-16 and LimPyr1 radiosensitization, as well as validate the safety and efficacy of this approach in vivo. National Research Foundation (NRF) Cancer Association of South Africa (CANSA) Medical Research Council (MRC) Research Committee (School of Medicine) of the University of Pretoria (RESCOM) Struwig-Germeshuysen Trust French Embassy La Ligne Foundation Arc Physiology PhD (Human Physiology) Restricted SDG-03: Good health and well-being 2019-04-05T07:22:00Z 2019-04-05T07:22:00Z 2019-04-05 2019 Thesis Nolte, EM 2019, Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells, PhD thesis, University of Pretoria, Pretoria, South Africa, Université Grenoble Alpes, Grenoble, France. http://hdl.handle.net/2263/68925 © 2019 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) Human Physiology Cell Biology Cancer Mitochondria Radiosensitization Radiation therapy Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title | Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title_full | Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title_fullStr | Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title_full_unstemmed | Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title_short | Pro-apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| title_sort | pro apoptotic and radiosensitizing potential of four candidate microtubule regulators in breast cancer cells |
| topic | UCTD Sustainable Development Goals (SDGs) Human Physiology Cell Biology Cancer Mitochondria Radiosensitization Radiation therapy |
| url | http://hdl.handle.net/2263/68925 |