Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

NF-κB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-κB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-κB activation. In human colon cancer cells, inhibition of NF-κB using 10 μM AS602868 induced a 30–50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-κB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg−1 AS602868 associated with 30 mg kg−1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-κB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFα on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours

Acute haemodynamic effects of IL-6 treatment in vivo: Involvement of vagus nerve in NO-mediated negative inotropism

Interleukin-6 (IL-6) reduces myocardial haemodynamics. However, the intrinsic mechanisms of IL-6 effects are not known. We hypothesized that nitric oxide (NO) synthesised by neuronal synthase (nNOS) can be the molecular mediator of IL-6-mediated cardiac effects. Thus, we investigated in vivo after IL-6 acute administration: (1) the role of NO pathway; (2) the importance of NO derived from nNOS located in intracardiac vagal ganglion in the anterior surface of the left ventricle. SpragueeDawley (SD) rats (225e250 g) were anaesthetized (sodium pentobarbital 30 mg/kg intraperitoneally administered) and ventilated. The effects of a single IL-6 bolus (100 mg/kg intravenously administered) were studied in four experimental groups: (a) IL-6 (nZ6), (b) IL-6 plus 30 mg/kg of L-NAME (an eNOS and nNOS inhibitor; nZ6), (c) IL-6 plus 25 mg/kg of 7-NI (a specific nNOS inhibitor; nZ6), (d) IL-6 plus vagal resection (nZ6). We evaluated the following parameters: mean aortic pressure (MAP), left ventricular end systolic pressure (LVESP), left ventricular positive peak dP/dt (PP dP/dt). Data are expressed as meanGsem. IL-6 caused a transient but significant reduction of MAP (21.8% of basal: p!0.05), LVESP (from 130G4.2 to 1056.5 mmHg: p!0.05) and PP dP/dt (from 5390G158 to 4400G223 mmHg/s, p!0.02). Concomitant treatment with L-NAME or 7-NI totally abolished IL-6 effects. Vagal resection significantly reduced the haemodynamic effects (MAP: 10% of basal: pZns; LVEDS: from 125G7.3 to 117G6.8 mmHg, p!0.05; PP dP/dt from 5500G150 to 5000G143 mmHg/s, p!0.05). We conclude that acute administration of IL-6 caused transient but significant cardiac negative inotropism. IL-6 haemodynamic effects are partly due to NO synthesised by nNOS located in vagal left ventricular ganglia. 2005 Elsevier Ltd. All rights reserved

Spatial correlations between Chl-a, SST, wind regime, and IMI in the southern Red Sea during summer.

<p><b><i>a)</i></b> Chl-a and wind regime. <b><i>b)</i></b> Chl-a and IMI. <b><i>c)</i></b> Chl-a and SST. <b><i>d)</i></b> SST and wind regime. The wind regime is defined as the averaged wind speed in the southern Red Sea (below 17°N) and the western Gulf of Aden (west of 46°E). The critical correlation value for a p<0.05 significance level with 11 degrees of freedom is <i>r</i> = 0.55.</p

Statistical models of summer Chl-a averages over the southern Red Sea.

<p><b><i>a)</i></b> Linear regression model of weekly Chl-a using IMI with a one-week lag as predictor. <b><i>b)</i></b> Linear regression model of weekly Chl-a using the wind speed averaged in the Gulf of Aden (west of 46°E) as predictor. <b><i>c)</i></b> Multivariate linear regression surface (white plane) of weekly Chl-a with the final predictors of wind speed and IMI. Positive and negative model errors on the data are represented with red and blue lines respectively. The solid black circles represent the datapoints.</p

<i>In situ</i> nutrient an velocity observations and model outputs of temperature and salinity

<p><b><i>a)</i></b><i>In situ</i> measurements of nutrient concentrations and mean velocity vectors at ~66m depth during September 2011; reprinted and adapted with permission from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168440#pone.0168440.ref018" target="_blank">18</a>]. <b><i>b)</i></b> <i>and</i> <b><i>c)</i></b> September climatological salinity and temperature at 65m depth, calculated from the MITgcm circulation model.</p

Vertical profiles of model outputs and <i>in situ</i> ship-borne observations, depicting the summer influx of colder, fresher, and nutrient-rich intermediate water masses (GAIW) into the southern Red Sea.

<p><b><i>a)</i></b> and <b><i>b)</i></b> Profiles of temperature and salinity climatologies during winter (Jan-Feb), obtained from the MITgcm circulation model, and averaged over the transect indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168440#pone.0168440.g001" target="_blank">Fig 1A</a>. <b><i>c)</i></b> and <b><i>d)</i></b> Similar profiles for the summer period (Jul-Aug). <b><i>e)</i></b> and <b><i>f)</i></b> <i>In situ</i> measurements of nutrient concentrations and salinity during the summer 2011, aggregated in cells of one-degree width and centered at approximate depths of 5, 10, 25, 50, 75, 100 and 200 m (marked by black diamonds on the y-axis).</p

Southern Red Sea simulated minimum salinity between 0m and 100m depth.

<p><b><i>a)</i></b> September climatology of the lowest salinity values observed between 0m and 100m depth—calculated from the MITgcm circulation model, and <b><i>b)</i></b> the depth at which these minimum salinity values occur.</p

Spatiotemporal distribution of remotely-sensed OC-CCI Chlorophyll in the Southern Red Sea (2000–2012).

<p><b><i>a)</i></b> Monthly climatology of Chl-a averaged in the southern Red Sea (blue-box area average, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168440#pone.0168440.g001" target="_blank">Fig 1A</a>). The red circular datapoints represent the individual months (2000–2012), while the grey shadow depicts the 90% confidence intervals of the climatology. <b><i>b)</i></b> Spatial distribution of Chl-a during summer; calculated based on monthly climatologies (May to August). <b><i>c)</i></b> Ratio of July to annual Chl-a observations, highlighting the higher concentrations of Chl-a in the southern Red Sea during July; computed from monthly composites between 2000 and 2012.</p

Summer SST climatology in the southern Red Sea, displaying evidences of cooling along the GAIW intrusion pathway.

<p><b><i>a)</i></b> Average SST difference between June and August (2000 to 2012), depicting a cooling of surface waters on the eastern shore of the southern Red Sea. <b><i>b)</i></b> SST monthly climatologies (solid lines) and individual monthly datapoints (solid circles), from 2000 to 2012 for the following regions (displayed in panel a): the rectangles represent areas in Farasan archipelago (red), central southern Red Sea (blue), and Dahlac archipelago (green).</p