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Title: The molecular effects of aspirin on NFκB in colorectal cancer
Author: Din, Farhat Vanessa Nasim
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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Aspirin induced a concentration-dependent decrease in viable cell number, paralleled by proportionate increases in apoptosis in five CRC cell lines. There was no consistent change in apoptosis in the five non-colonic cancer (NCC) cell lines studied. In CRC cell lines, aspirin-mediated apoptosis correlated with aspirin-induced IκBα degradation and NFκB nuclear translocation. In contrast, these changes in NFκB signalling were absent in NCC cell lines, paralleling the lack of changes in cell viability and apoptosis observed. This work shows that the aspirin-induced NFκB apoptotic response is relatively specific for CRC. Further elucidation of the molecular mechanism of this apparent differential senstiviity would lend insight into the mode of action of NSAIDs and identify molecular markers of response. Basal expression levels of NFκB constituents (IκB, p65), COX-2, and β-catenin did not correlate with susceptibility to apoptosis. This suggests that COX-2 and β-catenin are not appropriate as molecular markers of response. However, this work does emphasise the generality of the aspirin-induced NFκB apoptotic response in terms of CRC genotype. The influence of MMR and p53 status on the NFκB apoptotic response was determined, as these pathways are deranged in CRC, are implicated as NSAIDs targets and to potentially identify which subsets of CRC, with respect to genotype, are susceptible to aspirin mediated chemoprevention. The results show that the aspirin-induced NFκB apoptotic response occurs irrespective of MMR and p53 status. Biopsies were taken from rectal cancers inpatients before and after aspirin treatment for 1 week. There was IκB degradation in cytoplasmic extracts of rectal tumours after aspirin treatment. This indicates that aspirin modulates NFκB signalling in rectal cancer patients suggesting that this mechanism of action occurs in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available