Catherine McDermott

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.

Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed.

Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress

Pyocyanin, 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 ROS and deplete host antioxidant defence mechanisms. However, a causal role for oxidative stress has not yet been demonstrated conclusively. Parallel measures of ROS production, antioxidant levels and cytotoxicity provide convincing evidence that pyocyanin-induced cytotoxicity in A549 respiratory cells is mediated by acute ROS production and subsequent oxidative stress. Pyocyanin increased ROS levels in A549 cells as measured by the fluorescent H(2)O(2) probes Amplex Red and DCFH-DA. These effects were attenuated by the antioxidant N-acetylcysteine. Furthermore, pyocyanin-induced depletion of intracellular GSH levels 24h after exposure was also prevented by pre-treatment of cells with NAC. Under these conditions, NAC protected cells against pyocyanin-induced cytotoxicity as measured by resazurin reduction to resorufin and viable cell counts, strongly supporting a causal role for oxidative stress. Finally, we also show that pyocyanin-induced activation of the immune and inflammatory transcription factor NF-κB in A549 cells is likely mediated by increased ROS. This increased understanding of mechanisms underlying pyocyanin-induced cytotoxicity may ultimately lead to better strategies for reducing the virulence associated with chronic P. aeruginosa infection.

A review of the bioactivity of coffee, caffeine and key coffee constituents on inflammatory responses linked to depression

Coffee is a widely consumed beverage containing numerous biologically active constituents predominantly belonging to the polyphenol and alkaloid classes. It has been established that coffee has a beneficial effect on numerous disease states including depression. A number of prospective and retrospective cohort studies have assessed the effects of coffee consumption on the relative risk of developing major depressive disorder in humans. These studies have identified an inverse relationship between the consumption of caffeinated coffee and the risk of developing depression. Caffeine, chlorogenic acid, ferulic acid and caffeic acid, all important constituents of coffee, have been shown to possess biological activities that highlight a possible mechanistic link to the pathology of depression. This review aims to assess the evidence from the biological evaluation of these constituents of coffee on markers of inflammation associated with depression in in vitro and in vivo models of inflammation, neuroinflammation and depression. The ability of bioactive coffee constituents to modulate the parameters of neuroinflammation has been shown with caffeine having strong antioxidant properties in vitro, chlorogenic acid and caffeic acid having strong anti-inflammatory and antioxidant properties in vitro and ferulic acid having activities in in vivo animal models of depression.

Effects of Pseudomonas Aeruginosa Virulence Factor Pyocyanin on Human Urothelial Cell Function and Viability

PURPOSEnWe determined the effects of Pseudomonas aeruginosa virulence factor pyocyanin on human urothelial cell viability and function in vitro.nnnMATERIALS AND METHODSnRT4 urothelial cells were treated with pyocyanin (1 to 100 μM) for 24 hours. After exposure the treatment effects were measured according to certain end points, including changes in urothelial cell viability, reactive oxygen species formation, caspase-3 activity, basal and stimulated adenosine triphosphate release, SA-β-gal activity and detection of acidic vesicular organelles.nnnRESULTSnThe 24-hour pyocyanin treatment resulted in a concentration dependent decrease in cell viability at concentrations of 25 μM or greater, and increases in reactive oxygen species formation and caspase-3 activity at 25 μM or greater. Basal adenosine triphosphate release was significantly decreased at all tested pyocyanin concentrations while stimulated adenosine triphosphate release was significantly inhibited at pyocyanin concentrations of 12.5 μM or greater with no significant stimulated release at 100 μM. Pyocyanin treated RT4 cells showed morphological characteristics associated with cellular senescence, including SA-β-gal expression. This effect was not evident at 100 μM pyocyanin and may have been due to apoptotic cell death, as indicated by increased caspase-3 activity. An increase in acridine orange stained vesicular-like organelles was observed in RT4 urothelial cells after pyocyanin treatment.nnnCONCLUSIONSnExposure to pyocyanin alters urothelial cell viability, reactive oxygen species production and caspase-3 activity. Treatment also results in cellular senescence, which may affect the ability of urothelium to repair during infection. The virulence factor depressed stimulated adenosine triphosphate release, which to our knowledge is a novel finding with implications for awareness of bladder filling in patients with P. aeruginosa urinary tract infection.

Induction of inflammatory cytokines and alteration of urothelial ATP, acetylcholine and prostaglandin E2 release by doxorubicin

Intravesical treatment with cytotoxic drugs such as doxorubicin is associated with local adverse effects in bladder cancer patients. Here we investigate the effects of doxorubicin on urothelial release of ATP, acetylcholine and prostaglandin E(2), and production of inflammatory cytokines. Urothelial cells were treated with doxorubicin for 1h at 37 °C. Immediately or 24 h following treatment the level of ATP, acetylcholine and prostaglandin E(2) released under basal and stimulated conditions was measured and compared to release from vehicle treated control cultures. The presence of inflammatory cytokines, in culture medium was also assessed 24 h after doxorubicin pre-treatment. Immediately following treatment, stimulated ATP release was inhibited at doxorubicin concentrations ≥1 μg/ml and showed partial recovery at 24 h. Immediately following treatment, basal acetylcholine release was increased by doxorubicin at its clinical concentration (1 mg/ml), while a concentration-dependent decrease in stimulated acetylcholine release was observed. Twenty four hour after treatment, basal acetylcholine release was increased in culture treated with 0.01 mg/ml doxorubicin while stimulated acetylcholine release remained depressed. A significant increase in prostaglandin E(2) release was observed in cells immediately and 24 h after treatment with doxorubicin. A 5.5- and 2-fold increase in interleukin -8 and -1β secretion, respectively was detected 24 h following doxorubicin treatment. These findings indicate that inflammatory cytokines interleukin-8 and -1β are induced and urothelial mediator release is affected by treatment with doxorubicin at clinically relevant concentrations and durations of treatment. These changes may play a role in the adverse effects associated with intravesical doxorubicin treatment.

n-Hexane toxicity in Jurkat T-cells is mediated by reactive oxygen species

Here we assess the role of reactive oxygen species (ROS) formation in the manifestation of n-hexane toxicity in Jurkat T-cells and the chemo-protective potential of the antioxidants epigallocatechin-3-gallate (EGCG) and thymoquinone (TQ) against n-hexane toxicity in vitro. n-Hexane is an important industrial solvent and ambient air pollutant. Subchronic exposure to n-hexane results in a concentration-dependent increase in ROS formation with a corresponding decrease in Jurkat T-cell proliferation. Results from time–course studies indicate that ROS formation plays a causal role in n-hexane induced alterations in Jurkat T-cell proliferation and membrane integrity. Treatment of cells with EGCG, at a concentration reached in plasma, reduced the ROS formation caused by exposure to n-hexane and inhibited the decrease in cell proliferation. Similar effects were obtained with TQ. Both EGCG and TQ significantly reduced n-hexane-induced LDH leakage to control levels. The combined results show that oxidative stress plays a role in the development of n-hexane toxicity.

Toxicity of industrially relevant chlorinated organic solvents in vitro

The cytotoxic effects of 4 industrially important chlorinated organic solvents, dichloromethane (DCM), 1,2-dichloroethane (DCE), trichloroethylene (TCE), and tetrachloroethylene (PERC) in vitro, were investigated. Jurkat T cells were exposed to the solvents individually for 72 hours and changes in reactive oxygen species (ROS) formation, cell proliferation, intracellular free calcium concentration ([Ca2+]), and caspase-3 activity were measured. There was a concentration-dependent increase in the ROS formation and intracellular free [Ca2+] following exposure to each of the solvents. This was accompanied by a decrease in the cell proliferation. Solvent potency decreased in the following order: PERC > TCE > DCM > DCE. Caspase-3 activity was increased in a concentration-dependent manner by TCE and PERC but was not significantly altered by DCM or DCE. n-Acetyl-l-cysteine pretreatment showed that changes in the intracellular free [Ca2+] and caspase-3 activity were independent of ROS formation. However, increased ROS formation did play a causal role in the decreased cell proliferation observed.

Protection against radiotherapy-induced toxicity

Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents.