HIF-1alpha role in oxygen-dependent radio- and chemosensitivity
dc.check.chapterOfThesis | 3,4 | |
dc.check.embargoformat | E-thesis on CORA only | en |
dc.check.opt-out | Not applicable | en |
dc.check.reason | This thesis is due for publication or the author is actively seeking to publish this material | en |
dc.contributor.advisor | Allshire, Ashley | en |
dc.contributor.author | Gebolys, Kinga | |
dc.contributor.funder | Aid Cancer Treatment, Cork | en |
dc.date.accessioned | 2015-08-13T14:07:03Z | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014 | |
dc.description.abstract | Poor oxygenation (hypoxia) is a common characteristic of human solid tumours, and is associated with cell survival, metastasis and resistance to radio- and chemotherapies. Hypoxia-induced stabilisation of hypoxia-inducible factor-1α (HIF-1α) leads to changes in expression of various genes associated with growth, vascularisation and metabolism. However whether HIF-1α plays a causal role in promoting hypoxic resistance to antitumour therapies remains unclear. In this study we used pharmacological and genetic methods to investigate the HIF-1α contribution to radio- and chemoresistance in four cancer cell lines derived from cervical, breast, prostate and melanoma human tumours. Under normoxia or hypoxia (<0.2% or 0.5% oxygen) the cells were exposed to either a standard irradiation dose (6.2 Gy) or chemotherapeutic drug (cisplatin), and subsequent cell proliferation (after 7 days) was measured in terms of resazurin reduction. Oxygen-dependent radio- and chemosensitivity was evident in all wild type whereas it was reduced or abolished in HIF-1α (siRNA) knockdown cells. The effects of HIF-1α-modulating drugs (EDHB, CoCl2, deferoxamine to stabilise and R59949 to destabilise it) reflected both HIF-1α-dependent and independent mechanisms. Collectively the data show that HIF-1α played a causal role in our in vitro model of hypoxia-induced radioresistance whereas its contribution to oxygendependent sensitivity to cisplatin was less clear-cut. Although this behavior is likely to be conditioned by further biological and physical factors operating in vivo, it is consistent with the hypothesis that interventions directed at HIF-1α may improve the clinical effectiveness of tumour treatments. | en |
dc.description.status | Not peer reviewed | en |
dc.description.version | Accepted Version | |
dc.format.mimetype | application/pdf | en |
dc.identifier.citation | Gebolys, K. 2014. HIF-1alpha role in oxygen-dependent radio- and chemosensitivity. PhD Thesis, University College Cork. | en |
dc.identifier.endpage | 234 | |
dc.identifier.uri | https://hdl.handle.net/10468/1905 | |
dc.language.iso | en | en |
dc.publisher | University College Cork | en |
dc.rights | © 2014, Kinga Gebolys. | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
dc.subject | HIF-1alpha | en |
dc.subject | Cancer | en |
dc.subject | Hypoxia | en |
dc.subject | Oxygen-dependent radioresistance | en |
dc.subject | Oxygen-dependent chemoresistance | en |
dc.thesis.opt-out | false | |
dc.title | HIF-1alpha role in oxygen-dependent radio- and chemosensitivity | en |
dc.type | Doctoral thesis | en |
dc.type.qualificationlevel | Doctoral | en |
dc.type.qualificationname | PhD (Medicine and Health) | en |
ucc.workflow.supervisor | a.allshire@ucc.ie |
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