HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Spontaneous cognition in dysphoria: reduced positive bias in imagining the future.

Anomalies in future-oriented cognition are implicated in the maintenance of emotional disturbance within cognitive models of depression. Thinking about the future can involve mental imagery or verbal-linguistic mental representations. Research suggests that future thinking involving imagery representations may disproportionately impact on-going emotional experience in daily life relative to future thinking not involving imagery (verbal-linguistic representation only). However, while higher depression symptoms (dysphoria) are associated with impaired ability to deliberately generate positive relatively to negative imagery representations of the future (when instructed to do so), it is unclear whether dysphoria is associated with impairments in the tendency to do so spontaneously (when not instructed to deliberately generate task unrelated cognition of any kind). The present study investigated dysphoria-linked individual differences in the tendency to experience spontaneous future-oriented cognition as a function of emotional valence and representational format. Individuals varying in dysphoria level reported the occurrence of task unrelated thoughts (TUTs) in real time while completing a sustained attention go/no-go task, during exposure to auditory cues. Results indicate higher levels of dysphoria were associated with lower levels of positive bias in the number of imagery-based future TUTs reported, reflecting higher negative imagery-based future TUT generation (medium to large effect size), and lower positive imagery-based TUT generation (small to medium effect size). Further, this dysphoria-linked bias appeared to be specific in temporal orientation (future, not past) and representational format (imagery, not non-imagery). Reduced tendency to engage in positive relative to negative imagery-based future thinking appears to be implicated in dysphoria

Application of Mice Humanised for Cytochrome P450 CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants

Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy

A Targeted<em> in Vivo</em> SILAC Approach for Quantification of Drug Metabolism Enzymes:Regulation by the Constitutive Androstane Receptor

The modulation of drug metabolism enzyme (DME) expression by therapeutic agents is a central mechanism of drug-drug interaction and should be assessed as early as possible in preclinical drug development. Direct measurement of DME levels is typically achieved by Western blotting, qPCR, or microarray, but these techniques have their limitations; antibody cross-reactivity among highly homologous subfamilies creates ambiguity, while discordance between mRNA and protein expression undermines observations. The aim of this study was to design a simple targeted workflow by combining in vivo SILAC and label-free proteomics approaches for quantification of DMEs in mouse liver, facilitating a rapid and comprehensive evaluation of metabolic potential at the protein level. A total of 197 peptides, representing 51 Phase I and Phase II DMEs, were quantified by LC-MS/MS using targeted high resolution single ion monitoring (tHR/SIM) with a defined mass-to-charge and retention time window for each peptide. In a constitutive androstane receptor (Car) activated mouse model, comparison of tHR/SIM-in vivo SILAC with Western blotting for analysis of the expression of cytochromes P450 was favorable, with agreement in fold-change values between methods. The tHR/SIM-in vivo SILAC approach therefore permits the robust analysis of multiple DME in a single protein sample, with clear utility for the assessment of the drug-drug interaction potential of candidate therapeutic compounds. </p

A Cross-Cultural Study of Justice Sensitivity and Its Consequences for Cooperation

In Western samples, individuals differ systematically in the importance they assign to matters of justice and injustice, and dispositional Justice Sensitivity can be differentiated according to the perspectives of victim, observer, beneficiary, and perpetrator. In a cross-cultural comparison between the Philippines, Germany, and Australia (N ¼ 677 students), we investigated whether Justice Sensitivity can be equivalently described by these four perspectives, whether measurement instruments have invariant psychometric properties, and whether the psychological relevance of the Justice Sensitivity perspectives for cooperation behavior differs between these cultural contexts. The results of multigroup confirmatory factor analyses support weak measurement invariance and invariant associations between Justice Sensitivity perspectives and trust game decisions. Across cultures, victim sensitivity predicted reluctance to cooperate under threat of exploitation, and observer, beneficiary, and perpetrator sensitivities predicted cooperation under temptation. Our study extends insight into Justice Sensitivity to underresearched cultural contexts of urban and rural Philippines

Absence of evidence or evidence of absence: Reflecting on therapeutic implementations of attentional bias modification

Attentional bias modification (ABM) represents one of a number of cognitive bias modification techniques which are beginning to show promise as therapeutic interventions for emotional pathology. Numerous studies with both clinical and non-clinical populations have now demonstrated that ABM can reduce emotional vulnerability. However, some recent studies have failed to achieve change in either selective attention or emotional vulnerability using ABM methodologies, including a recent randomised controlled trial by Carlbring et al. Some have sought to represent such absence of evidence as a sound basis not to further pursue ABM as an online intervention. While these findings obviously raise questions about the specific conditions under which ABM procedures will produce therapeutic benefits, we suggest that the failure of some studies to modify selective attention does not challenge the theoretical and empirical basis of ABM. The present paper seeks to put these ABM failure s in perspective within the broader context of attentional bias modification research. In doing so it is apparent that the current findings and future prospects of ABM are in fact very promising, suggesting that more research in this area is warranted, not less

Book Reviews

PRACTICAL STUDENT OBSTETRICS Bende, S &amp; Tindall, VR Heinemann, 1980 pp; 435. £12.50ESSENTIALS OF DERMATOLOGY J.L. Burton, Churchill Livingstone. 1980. pp. 196. £3.95ESSENTIAL PAEDIATRICS Hull, D. &amp; Johnston, D.l. Churchill Livingstone, 1981 pp.305. £10.00PRACTICAL PROCEDURES IN CLINIC AL MEDICINE Michael J. Ford and John F. Munro Churchill Livingstone 1980 pp. 128. £4.25LECTUR E NOTES ON CLINICAL ONCOLOGY: Hancock, B.W. &amp; Bradshaw, J.D.Blackwell, 1981.pp. 176. £5.50INTRODUCING ANATOMY J.D. Lever London: William Heinemann Medical Books Ltd. 1980.pp. 288. £7.95