Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species. The limitations of studies are, to date, focused on the localized effect of the release of pyocyanin (PCN). It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect. This review highlights the possible manifestations of PCN exposure; however, most studies to date are in vitro. Further high quality in vivo studies are needed to fully assess the physiological manifestations of PCN exposure on the various body systems.

This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

Prazosin and doxazosin demonstrated cytotoxic actions on both castration-resistant PC-3 and androgen-sensitive LNCap prostate cancer cells. The mechanisms involved included changes in a number of proliferation and apoptosis regulatory proteins. The role of autophagy depended on the cell type, but contributed to cell death in PC3 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.

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