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Henderson D.J.P.,University of Glasgow | Byrne A.,University of Glasgow | Dulla K.,Philips | Jenster G.,Erasmus MC | And 3 more authors.
British Journal of Cancer | Year: 2014

Background: Isoforms of the PDE4 family of cAMP-specific phosphodiesterases (PDEs) are expressed in a cell type-dependent manner and contribute to underpinning the paradigm of intracellular cAMP signal compartmentalisation. Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression and uncover a role in controlling prostate cancer cell proliferation. Methods: PDE4 transcripts from 19 prostate cancer cell lines and xenografts were quantified by qPCR. PDE4D7 expression was further investigated because of its significant downregulation between androgen-sensitive (AS) and androgen-insensitive (AI) samples. Western blot analysis, PDE activity assay, immunofluorescent staining and cAMP responsive FRET assays were used to investigate the sub-plasma membrane localisation of a population of PDE4D7 in VCaP (AS) and PC3 (AI) cell lines. Disruption of this localisation pattern using dominant-negative protein expression and siRNA knockdown showed that PDE4D7 acts in opposition to proliferative signalling as assessed by electrical impedance-based proliferation assays. Results: Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression. PDE4D7 is highly expressed in AS cells and starkly downregulated in AI samples. The significance of this downregulation is underscored by our finding that PDE4D7 contributes a major fraction of cAMP degrading PDE activity tethered at the plasma membrane and that displacement of PDE4D7 from this compartment leads to an increase in the proliferation of prostate cancer cells. PDE4D7 mRNA expression is not, however, directly regulated by the androgen receptor signalling axis despite an overlapping genomic structure with the androgen responsive gene PART1. PDE4D7, which locates to the plasma membrane, acts to supress aberrant non-steroidal growth signals within the prostate or AS metastasis. Conclusions: PDE4D7 expression is significantly downregulated between AS and AI cell phenotypes. This change in expression potentially provides a novel androgen-independent biomarker and manipulation of its activity or its expression may provide therapeutic possibilities and insights into contributory aspects of the complex molecular pathology of prostate cancer. © 2014 Cancer Research UK.

Prescott T.A.K.,Royal Botanic Gardens | Panaretou B.,Institute of Pharmaceutical Science | Veitch N.C.,Royal Botanic Gardens | Simmonds M.S.J.,Royal Botanic Gardens
FEBS Letters | Year: 2014

The phosphatase enzyme calcineurin controls gene expression in a variety of biological contexts however few potent inhibitors are currently available. A screen of 360 plant extracts for inhibition of calcineurin-dependent gene expression in the model organism Saccharomyces cerevisiae identified the compound 3,4,5-trimethoxybenzyl isothiocyanate as an inhibitor. The compound was subsequently shown to inhibit human calcineurin via a mixed inhibition mechanism. To gain further mechanistic insight a yeast haploinsufficiency screen of 1152 deletion strains was carried out using a novel liquid medium screening method. The resulting haploinsufficiency profile is similar to that reported for the known calcineurin inhibitor FK506.

Jenner P.,Institute of Pharmaceutical Science | McCreary A.C.,Brains On Line | Scheller D.K.A.,UCB Pharma
Journal of Neural Transmission | Year: 2011

The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD. © 2011 Springer-Verlag.

Anthopoulou E.,Institute of Pharmaceutical Science
Pharmaceutical Medicine | Year: 2016

Electronic cigarettes are nicotine delivery devices that have rapidly penetrated into the market since their invention in 2003. Their remarkably rapid spread has raised questions concerning their safety and efficacy as smoking cessation aids. However, despite this uncertainty, the number of users is increasing, especially among smokers and ex-smokers who are trying to keep away from tobacco cigarettes. Several chemical studies have been conducted and a safer profile compared with tobacco cigarettes has been recognized. Clinical and population studies have given a first insight into the efficacy of e-cigarettes as smoking cessation aids, supporting their potential. Nonetheless, these preliminary findings cannot lead to reliable conclusions about their long-term safety and efficacy and further research is warranted. The burden of tobacco-related diseases is a major cause of morbidity and mortality worldwide and further measures are needed in order to reduce tobacco harm. At the moment, e-cigarettes are categorized as consumer products in the UK because the Medicines and Healthcare Products Regulatory Agency’s (MHRA’s) recommendation to regulate e-cigarettes as medicines did not get the adequate response; however, very soon e-cigarettes will be regulated under the EU’s Tobacco Product Directive. E-cigarettes are widely used and the preliminary findings on safety and efficacy, in combination with the need for new tobacco harm reduction strategies, suggest that the investigation of e-cigarettes’ potential as a smoking cessation aid is imperative. © 2016, Springer International Publishing Switzerland.

Yamada K.,Kyowa Hakko Kirin Co. | Kobayashi M.,Kyowa Hakko Kirin Co. | Mori A.,Kyowa Hakko Kirin Co. | Jenner P.,Institute of Pharmaceutical Science | Kanda T.,Kyowa Hakko Kirin Co.
Pharmacology Biochemistry and Behavior | Year: 2013

Rationale Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. Objective We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. Results Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16 mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08 mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. Conclusions Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic-pituitary-adrenal axis. © 2013 Published by Elsevier Inc.

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