AbstractEarly stage prostate cancer is highly manageable using definitive radicalprostatectomy and/ or radiotherapy techniques. Unfortunately, for some men,transition to castrate-resistant prostate cancer is both inevitable and incurable with few life-extending therapies available. Therefore, there is an urgent need for novel agents to improve the oncological and survival outcomes for these last-resort patients.One such modality may be α1-adrenoceptor antagonists. Clinically, some of these drugs reportedly increase benign and cancerous prostatic apoptosis. In vitro studies indicate that this anticancer effect occurs via !1-adrenoceptor independent mechanisms. However, the cytotoxic profile of these drugs have yet to be fully characterised, including whether these agents may be useful in improving anticancer treatment efficacy. To address the gaps in literature, the relative cytotoxic potencies and underlying cell death mechanisms (apoptosis and autophagy) were determined for six 1-adrenoceptor antagonists on castrate-sensitive and castrate-resistant prostate cancer cells. Molecular mechanisms were explored using immunoassays. The effectsof these drugs were also investigated on normoxic or hypoxic irradiated prostatecancer cells to mimic outer and inner portions of a solid tumour. In an adjunct study, comparisons between the cytotoxic profile of doxazosin and the chemotherapeutic mitomycin c were made in an in vitro model of bladder cancer intravesical therapy.Overall, prazosin and doxazosin were found to be equipotent and were the mostpotent of all investigated drugs by inducing apoptosis and/or autophagy in a cell typedependent manner. This cytotoxic effect was attributed to decreased mTOR/p70S6K signalling coupled with increases in p27 and p38 mitogen-activated protein kinase. Prazosin was also found to selectively radiosensitise hypoxic prostate cancer cells. This effect was characterised by increased reactive oxygen species and suppression of HIF-1! accumulation, further implicating mTOR-signalling as an underlying cytotoxic mechanism. Exploration of additional novel uses of these drugs revealed that doxazosin was 6-times more toxic than mitomycin C on bladder cancer cells in modelling of intravesical therapy. Taken together, these findings indicate that prazosin/doxazosin have potent cytotoxic actions in prostate cancer cells that are characterised by induction of apoptosis and autophagy, possibly by inhibition of themTOR-signalling cascade. This is the first report of radiosensitising effects of these drugs in prostate cancer cells, suggesting that these agents may have novel clinical benefits for patients undergoing radiotherapy. Likewise, the preliminarily findings of this thesis suggest that these drugs may be a novel alternative intravesical treatment option for bladder cancer and warrants further investigation.
|Date of Award||8 Oct 2016|
|Supervisor||Catherine McDermott (Supervisor), Russ Chess-Williams (Supervisor) & Shailendra Anoopkumar-Dukie (Supervisor)|
Quinazoline-based Alpha1-Adrenoceptor Antagonists and Prostate Cancer
Forbes, A. (Author). 8 Oct 2016
Student thesis: Doctoral Thesis