In this study we investigated the cytotoxic effects of the isoflavone molecule Phenoxodiol, on the prostate cancer cell lines LNCaP, DU145 and PC3. LNCaP cells represented a hormone responsive early stage prostate cancer while DU145 and PC3 cells represented late stage hormone refractory and chemoresistant prostate cancer. We investigated the cytotoxic effects induced in these cell lines over a period of 24 or 48 hours of treatment with 10μM and 30μM doses of phenoxodiol. Cells exhibited significant cytotoxicity and mitochondrial depolarisation in response to phenoxodiol treatment. The study established LNCaP and DU145 cells responded apoptotically to treatment, while PC3 cells respond necrotically. After confirming cytotoxic responses the underlying signalling mechanisms were investigated which revealed that phenoxodiol was not inducing cell death via an increase in Caspase-3 activity, in two of three cell lines, and the apoptotic machinery of the cells responded in a varied manner between cell lines. Phenoxodiol was revealed to work via Caspase independent actions and the effect of the mitochondrial signalling molecules was not consistently altered in response to treatment indicating phenoxodiol did not directly target intrinsic or extrinsic caspase signalling pathways. We then investigated the effects of phenoxodiol on the cell cycle where treatment groups exhibited a significant increase in G1 and S phase populations and a corresponding decrease in G2 phase populations. The underlying signalling was investigated and it was determined that p21WAF1 expression was increased consistently between the three cell lines in response to treatment.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2012|