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Title: Understanding the potential mechanisms of action of dietary prostate carcinogens
Author: Graham, Oliver William
ISNI:       0000 0004 7427 7213
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Prostate cancer is the most commonly diagnosed cancer in males in the UK, and while the precise aetiology of prostate cancer remains unknown, risk factors such as age and lifestyle have been identified. Consumption of a ‘western’ diet rich in well-done red meat has been implicated in the development of prostate cancer, due to the appreciable amounts of carcinogenic material found in these foods. Two common dietary carcinogens are benzo[a]pyrene (B[a]P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), both of which have been identified as possible prostate mutagens. Another possible risk factor for prostate cancer is inflammation (a common condition in the prostate), specifically interleukin- 6 (IL-6) which is found elevated in the serum of prostate cancer patients. The underlying mechanisms behind the influence of dietary carcinogens and inflammation on the development of prostate cancer remain elusive, with limited knowledge about how inflammation may alter the modes of action of dietary carcinogens in the prostate. I hypothesised that IL-6 may alter the activation of B[a]P and PhIP, resulting in phenotypic alterations to prostate cells that are associated with cancer development. Using an in vitro, cell culture based model, the current project reported findings that both B[a]P and PhIP induce alterations in prostate cell migration while demonstrating genotoxic potential. Moreover, mixtures of B[a]P and PhIP induced significantly more genetic damage than either chemical in isolation, suggesting that interplay during simultaneous exposure in vivo may result in higher levels of DNA damage in the prostate. Further, PhIP-induced genotoxicity appeared to be a result of cytochrome P450-mediated production of reactive oxygen species. Finally, my data indicate that IL-6 increases B[a]P-mediated genetic damage, suggesting that activation of B[a]P in prostate cells may be altered by inflammatory cytokines such as IL-6, but more work is needed in order to verify this interaction. These novel findings must be explored in greater depth in order to fully understand how these factors interact in the prostate.
Supervisor: Gooderham, Nigel J. Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral