HIF-1alpha role in oxygen-dependent radio- and chemosensitivity

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dc.check.chapterOfThesis3,4
dc.check.embargoformatE-thesis on CORA onlyen
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorAllshire, Ashleyen
dc.contributor.authorGebolys, Kinga
dc.contributor.funderAid Cancer Treatment, Corken
dc.date.accessioned2015-08-13T14:07:03Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractPoor 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.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGebolys, K. 2014. HIF-1alpha role in oxygen-dependent radio- and chemosensitivity. PhD Thesis, University College Cork.en
dc.identifier.endpage234
dc.identifier.urihttps://hdl.handle.net/10468/1905
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Kinga Gebolys.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectHIF-1alphaen
dc.subjectCanceren
dc.subjectHypoxiaen
dc.subjectOxygen-dependent radioresistanceen
dc.subjectOxygen-dependent chemoresistanceen
dc.thesis.opt-outfalse
dc.titleHIF-1alpha role in oxygen-dependent radio- and chemosensitivityen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisora.allshire@ucc.ie
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