Quinazoline alpha-adrenoreceptor blockers as an adjunct cancer treatment: From bench to bedside.

Drug repurposing has been increasingly used by both researchers and clinicians to identify new cancer treatments. The alpha-1 adrenoreceptor blockers are a class of drugs that have been used for many years in the treatment of hypertension and benign prostatic hyperplasia. Some of the drugs in this class, notably the quinazoline derivatives, have been found to display cytotoxic properties, identifying them as potential options in the treatment of cancer. This review will examine the currently available evidence that investigates the cytotoxic and anti-cancer properties of these agents, the mechanisms behind these properties and how the alpha-1 blockers fit within current cancer therapies. It aims to answer the question of whether these agents can go from the laboratory bench top into cancer clinics.

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

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.

Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa.

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.

Relative cytotoxic potencies and cell death mechanisms of α1 -adrenoceptor antagonists in prostate cancer cell lines.

BACKGROUND: Some α1 -adrenoceptor antagonists possess anti-cancer actions that are independent of α1 -adrenoceptors and the aim of these studies was to assess the relative cytotoxic potencies of α1 -adrenoceptor antagonists and the mechanisms involved in these actions. METHODS: PC-3 and LNCap human prostate cancer cells were exposed to α1 -adrenoceptor antagonists (0.01-100 µM) and cell survival assessed after 24-72 hr. The levels of apoptosis, autophagy and stress related proteins were also determined. RESULTS: The relative cytotoxic potency order was prazosin = doxazosin > terazosin = silodosin = alfuzosin > tamsulosin on both cell types, but LNCaP cells were significantly more sensitive to these effects than PC-3 cells. Prazosin and doxazosin increased levels of apoptotsis and autophagy in both cell lines, and activated EphA2 receptors in PC-3 cells. Autophagy contributed to survival of LNCaP, but promoted cell death in PC-3 cells. Treatment with prazosin (30 µM) altered the expression of several cell stress-related proteins: elevating phospho-p38α and reducing S6 kinase in both cell lines. Surprisingly some proteins were differentially affected in the two prostate cancer cell lines: Akt and p27 increasing and HIF-1α decreasing in LNCap cells but not PC-3, while ADAMTS1 was increased in PC-3 cells only. CONCLUSIONS: 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.

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.

ERK1/2 activation modulates pyocyanin-induced toxicity in A549 respiratory epithelial cells.

Pyocyanin (PCN), a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate oxidative stress. However mechanisms underlying PCN-induced oxidative injury remain unclear. Although oxidative stress and subsequent MAPK signaling has been shown to modulate cell death in other models, its role in PCN-induced cytotoxicity remains unknown. Therefore the aim of this study was to investigate the role of redox-sensitive MAPK in PCN-induced toxicity in A549 cells. Here we show that PCN (50µM) rapidly increased ERK1/2 phosphorylation after 5min. Pre-treatment of A549 cells with the MEK1/2 inhibitor U0126 (10µM) decreased PCN-induced ERK1/2 phosphorylation and protected cells against apoptosis and cell injury suggesting a role for ERK signalling. In contrast, JNK and p38 MAPK phosphorylation remained unchanged following exposure to PCN and pretreatment with either the JNK or p38 MAPK inhibitors (10µM SP600125 and 10µM SB203580, respectively) did not afford protection against PCN toxicity. This would suggest that PCN-induced cytotoxicity appears to occur independently of JNK and p38 MAPK signaling pathways. Finally, although we confirm that oxidative stress contributes to PCN-induced toxicity, our data suggest the contribution of oxidative stress is independent of ERK1/2 signaling. These findings may provide insight for novel targeted therapies to reduce PCN-mediated lung injury in patients with chronic P. aeruginosa respiratory infections.