Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579761
Title: The role of radiation-induced cell death and resistance in non-small cell lung cancer
Author: Lawlor, Martin Paul
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Abstract:
40% of all patients cured of cancer receive radiation therapy as a part of their treatment. However, acquired or intrinsic resistance remains a major obstacle in increasing this already effective treatment, particularly in the treatment of NSCLC. Therefore, new approaches are needed to increase its biological effectiveness. A major pathway of tumour radiation resistance is through inactivation of cell death pathways. Our aims were to develop and characterize an in vitro model system of NSCLC radiation resistance following fractionated exposures that mimic clinical treatment regimes, as well as, to manipulate the apoptotic and autophagic death pathways as a means to sensitize NSCLC to radiotherapy. We found that exposure to a series of fractionated treatments resulted in acquired resistance of NSCLC cell lines to IR. In addition, we found that cisplatin-resistant NSCLC lines, developed following similar fractionated exposures, were also radiation-resistant. Our results suggest that there may be common pathways of radiation/cisplatin-resistance, and by studying modes of cell death, we can target under-utilized cell death pathways to improve the efficacy of radiation treatment. We modulated apoptosis induction by inhibiting caspases (Z-VAD-fmk) and BcI-2 anti-apoptotic proteins (Obatoclax). Our results showed that apoptosis plays a minor role in radiation-induced cell death. While caspase and BcI-2 anti-apoptotic protein inhibition resulted in changes in apoptosis, we observed no change in clonogenic survival. We then targeted autophagy induction through the inhibition of mTOR by Rad001. We found that mTOR inhibition resulted in decreased autophagy, suggesting that autophagy was being utilized as a survival mechanism in NSCLC, thus causing a significant reduction in cell survival following IR treatment. However, in combination with IR, both Obatoclax and Rad001 did not cause an additive or synergistic increase in cell death. Cell cycle analyses revealed that alternative mechanisms of cell death such as mitotic catastrophe and senescence may play a more pivotal role in IR-induced cell death. Altogether, our studies reveal that NSCLC cells may undergo multiple cell death pathways in response to IR. Our fractionated model system, as a mimic of clinical acquired radiation-resistance, will facilitate further examination of the mechanisms of radiation resistance. And our findings suggest that manipulation of alternative death pathways (such as mitotic catastrophe and senescence) in NSCLC needs further examination as a target for tumour sensitization to radiotherapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.579761  DOI: Not available
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