Prazosin but Not Tamsulosin Sensitises PC-3 and LNCaP Prostate Cancer Cells to Docetaxel

Background/Aims: Docetaxel is currently the first-line chemotherapeutic agent available for the treatment of patients with advanced prostate cancer (PCa). While docetaxel has been shown to modestly improve survival times for patients; they also experience significant docetaxel-induced toxicities. If treatment failure occurs, there are currently limited alternatives that show survival benefits for patients and therefore there is an urgent need for adjunct therapies. Some quinazoline-based alpha1-adrenoceptor (ADR) antagonists have previously been shown to have cytotoxic actions in PCa cells, but there is no research into their effects on docetaxel-induced toxicity. Therefore, the aim of this study was to determine if the quinazoline ADR, prazosin influenced the sensitivity of PCa cells to docetaxel in vitro. We hypothesised that prazosin, but not tamsulosin, in combination with docetaxel would possess synergistic cytotoxic actions on PC-3 and LNCaP PCa cells. Methods: PC-3 and ­LNCaP cells were pre-treated (1 h) with prazosin (30 µmol/L) or tamsulosin (30 µmol/L), followed by docetaxel (12.5–100 μmol/L) for 24 h. Docetaxel-induced toxicity was measured in terms of changes in cell proliferation, autophagy, apoptosis and the production of reactive oxygen species (ROS). Results: Prazosin sensitised both cell lines (PC-3 and LNCaP) to docetaxel-induced toxicity. This effect appears to be mediated by autophagy and may also involve apoptosis. These sensitising effects of prazosin appear to be largely independent of ROS production. In contrast, tamsulosin did not affect docetaxel-induced toxicity. Conclusion: We have shown for the first time that prazosin increases docetaxel-induced toxicity in PC-3 and LNCaP cells. Prazosin may therefore offer a viable treatment option in combination with docetaxel in metastatic PCa.Griffith Health, School of Pharmacy and PharmacologyNo Full Tex

Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel-induced toxicity in PC-3 and LNCaP prostate cancer cells

Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5 mM) and then exposed to various concentrations (0–100 μM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3-methyladenine (5 mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines.No Full Tex