Antimitotics are used in cancer chemotherapy for the treatment of cancers such as breast, ovarian, lung and prostate. Despite the success of agents such as Taxol, problems have emerged such as side effects, resistance and the lack of ability to predict patient responsiveness. As a result, a class of second-generation inhibitors have been developed with the aim to overcome or improve these issues. Such inhibitors target proteins and kinases involved in the control of mitosis and the cell cycle. However, these have yet to be clinically successful and therefore, this highlights the requirement for an increased understanding of the mitotic process and how antimitotics truly elicit their action. Reasons for the lack of efficacy may be due to the absence of biomarkers to stratify patients into those likely to respond to treatment. It may also be possible that other targets are required. Our understanding of the action of antimitotics is therefore paramount to improving cancer chemotherapy. By exploiting mitosis and understanding what happens when mitosis goes wrong, this thesis aims to explore new and improved methods of targeting, but also proposes to improve our understanding of the consequences of aberrant mitoses through the use of small molecule inhibitors. In the first case the thesis investigated the targeting of the spindle checkpoint protein Bub1 with 2OH-BNPP1, where previously inhibitors against the kinase were not acknowledged. However the inhibitor used was not effective in cells and therefore further experimentation was not possible. Secondly, to explore the consequences of mitotic perturbation, an assay to explore aneuploidy was established. To do this a Cenp-E inhibitor GSK923295 was synthesised, which was subsequently used in assays with the Mps1 inhibitor AZ3146 to generate aneuploidy progeny. The Cenp-E inhibitor was then used as an antimitotic agent in the final chapter to explore the mechanism of action of mitotic blockers and drivers often used in cell biology and clinical settings. Evidence suggests that the intrinsic apoptotic pathway is activated upon exposure to these agents. With focus on this pathway, the importance of Bcl-xL on cell survival was considered, revealing particular importance in the post-mitotic response. Ultimately, this thesis should contribute to devising new and improved anti-cancer strategies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:703036 |
| Date | January 2017 |
| Creators | Bennett, Ailsa |
| Contributors | Jackson, Dean ; Taylor, Stephen |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/exploiting-mitosis-to-improve-anticancer-strategies(b29182a1-2f37-47cb-8dc5-cbef76786dd2).html |
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