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Oncology Letters Oct 2016Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with...
Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.
PubMed: 27698831
DOI: 10.3892/ol.2016.4992 -
Physiological Reports Jun 2016Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions....
Sine-wave electrical stimulation initiates a voltage-gated potassium channel-dependent soft tissue response characterized by induction of hemocyte recruitment and collagen deposition.
Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions. Macrophages play a critical role in this wound healing process beginning at the onset of tissue injury. Understanding the signaling mechanisms involved in macrophage recruitment to the wound site is an essential step for developing more effective clinical therapies. Macrophages are known to respond to electrical fields, but the underlying cellular mechanisms mediating this response is unknown. This study demonstrated that low-amplitude sine-wave electrical stimulation (ES) initiates a soft tissue response in the absence of injury in Procambarus clarkii This cellular response was characterized by recruitment of macrophage-like hemocytes to the stimulation site indicated by increased hemocyte density at the site. ES also increased tissue collagen deposition compared to sham treatment (P < 0.05). Voltage-gated potassium (KV) channel inhibition with either 4-aminopyridine or astemizole decreased both hemocyte recruitment and collagen deposition compared to saline infusion (P < 0.05), whereas inhibition of calcium-permeable channels with ruthenium red did not affect either response to ES Thus, macrophage-like hemocytes in P. clarkii elicit a wound-like response to exogenous ES and this is accompanied by collagen deposition. This response is mediated by KV channels but independent of Ca(2+) channels. We propose a significant role for KV channels that extends beyond facilitating Ca(2+) transport via regulation of cellular membrane potentials during ES of soft tissue.
Topics: Action Potentials; Animals; Astacoidea; Calcium Channels; Collagen; Electric Stimulation; Hemocytes; Muscles; Potassium Channels, Voltage-Gated
PubMed: 27335435
DOI: 10.14814/phy2.12832 -
EBioMedicine Jul 2016Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD)...
Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD) library for cytotoxicity against NSCLC cells and identified several CAD antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy.
Topics: A549 Cells; Adult; Apoptosis; Astemizole; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cations; Cell Line, Tumor; Cohort Studies; Denmark; Drug Repositioning; Drug Resistance, Neoplasm; Histamine Antagonists; Humans; Loratadine; Lung Neoplasms; Lysosomes; Proportional Hazards Models; Registries; Survival Rate
PubMed: 27333030
DOI: 10.1016/j.ebiom.2016.06.013 -
Journal of Pharmacological Sciences Jun 2016Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the...
Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.
Topics: Animals; Antineoplastic Agents; Astemizole; Atrioventricular Block; Disease Models, Animal; Dogs; Female; Male; Torsades de Pointes
PubMed: 27262902
DOI: 10.1016/j.jphs.2016.04.024 -
Scientific Reports Apr 2016The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting...
The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that a reduction of FET proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired motor phenotypes. FET proteins are also involved in the regulation of lifespan and stress resistance, acting partially through the insulin/IGF-signalling pathway. We propose that FET proteins are involved in the maintenance of lifespan, cellular stress resistance and neuronal integrity.
Topics: Animals; Astemizole; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Insulin; Longevity; Mutation; Neurons; Signal Transduction; Somatomedins; Stress, Physiological
PubMed: 27117089
DOI: 10.1038/srep25159 -
Molecular Imaging 2016Early clinical results of two tau tracers, [(18)F]T808 and [(18)F]T807, have recently been reported. In the present study, the biodistribution, radiometabolite... (Comparative Study)
Comparative Study
Early clinical results of two tau tracers, [(18)F]T808 and [(18)F]T807, have recently been reported. In the present study, the biodistribution, radiometabolite quantification, and competition-binding studies were performed in order to acquire comparative preclinical data as well as to establish the value of T808 and T807 as benchmark compounds for assessment of binding affinities of eight new/other tau tracers. Biodistribution studies in mice showed high brain uptake and fast washout.In vivoradiometabolite analysis using high-performance liquid chromatography showed the presence of polar radiometabolites in plasma and brain. No specific binding of [(18)F]T808 was found in transgenic mice expressing mutant human P301L tau. In semiquantitative autoradiography studies on human Alzheimer disease slices, we observed more than 50% tau selective blocking of [(18)F]T808 in the presence of 1 µmol/L of the novel ligands. This study provides a straightforward comparison of the binding affinity and selectivity for tau of the reported radiolabeled tracers BF-158, BF-170, THK5105, lansoprazole, astemizole, and novel tau positron emission tomography ligands against T807 and T808. Therefore, these data are helpful to identify structural requirements for selective interaction with tau and to compare the performance of new highly selective and specific radiolabeled tau tracers.
Topics: Alzheimer Disease; Animals; Benzimidazoles; Brain Chemistry; Fluorine Radioisotopes; Humans; Mice; Mice, Transgenic; Mutation; Plasma; Positron-Emission Tomography; Pyrimidines; Radiopharmaceuticals; Tissue Distribution; tau Proteins
PubMed: 27030397
DOI: 10.1177/1536012115624920 -
ACS Medicinal Chemistry Letters Mar 2016The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule...
The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels.
PubMed: 26985309
DOI: 10.1021/acsmedchemlett.5b00360 -
PloS One 2016An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast...
An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity.
Topics: Antineoplastic Agents; Cell Survival; Cluster Analysis; Computational Biology; Computer Simulation; Databases, Factual; Datasets as Topic; Drug Repositioning; Drug Screening Assays, Antitumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma; High-Throughput Screening Assays; Humans; Neoplasms; Reproducibility of Results; Signal Transduction; Transcriptome
PubMed: 26954019
DOI: 10.1371/journal.pone.0150460 -
Marine Drugs Oct 2015Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5-7, and 9-12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their...
Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5-7, and 9-12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher's and Marfey's methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4-6 and 8-12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds.
Topics: Alkaloids; Animals; Astemizole; Bradycardia; Cardiovascular Agents; Circular Dichroism; Heart Rate; Neovascularization, Physiologic; Penicillium; Secondary Metabolism; Zebrafish
PubMed: 26506361
DOI: 10.3390/md13106489 -
PloS One 2015There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine...
BACKGROUND
There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.
AIM
To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.
METHODS
We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.
RESULTS
Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.
CONCLUSIONS
Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.
Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Arrhythmias, Cardiac; Databases, Factual; Drug Utilization; Europe; Histamine H1 Antagonists; Humans; Pharmacovigilance
PubMed: 25785934
DOI: 10.1371/journal.pone.0119551