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Scientific Reports Mar 2017Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in... (Meta-Analysis)
Meta-Analysis
Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.
Topics: Aged; Cinnarizine; Clofazimine; Digitoxigenin; Drug Therapy; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Melanoma; Microarray Analysis; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Uveal Neoplasms
PubMed: 28303962
DOI: 10.1038/srep44564 -
Basic & Clinical Pharmacology &... Jul 2017
Topics: Aged; Aged, 80 and over; Cardiotonic Agents; Digitoxin; Digoxin; Drug Substitution; Female; Humans; Male; Middle Aged; Norway; Retrospective Studies
PubMed: 28235161
DOI: 10.1111/bcpt.12770 -
Journal of Natural Products Mar 2017(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an...
(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na/K-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Ovarian Epithelial; Cardiac Glycosides; Digoxin; Female; HT29 Cells; Humans; Molecular Structure; NF-kappa B; Neoplasms, Glandular and Epithelial; Ouabain; Ovarian Neoplasms; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Stereoisomerism
PubMed: 28234008
DOI: 10.1021/acs.jnatprod.6b01150 -
Oncotarget Feb 2017Cardiac glycosides are well known in the treatment of cardiovascular diseases; however, their application as treatment option for cancer patients is under discussion. We...
A new semisynthetic cardenolide analog 3β-[2-(1-amantadine)- 1-on-ethylamine]-digitoxigenin (AMANTADIG) affects G2/M cell cycle arrest and miRNA expression profiles and enhances proapoptotic survivin-2B expression in renal cell carcinoma cell lines.
Cardiac glycosides are well known in the treatment of cardiovascular diseases; however, their application as treatment option for cancer patients is under discussion. We showed that the cardiac glycoside digitoxin and its analog AMANTADIG can inhibit the growth of renal cell carcinoma (RCC) cell lines and increase G2/M cell cycle arrest. To identify the signaling pathways and molecular basis of this G2/M arrest, microRNAs were profiled using microRNA arrays. Cardiac glycoside treatment significantly deregulated two microRNAs, miR-2278 and miR-670-5p. Pathway enrichment analysis showed that all cardiac glycoside treatments affected the MAPK and the axon guidance pathway. Within these pathways, three genes, MAPK1, NRAS and RAC2, were identified as in silico targets of the deregulated miRNAs. MAPK1 and NRAS are known regulators of G2/M cell cycle arrest. AMANTADIG treatment enhanced the expression of phosphorylated MAPK1 in 786-O cells. Secondly, we studied the expression of survivin known to be affected by cardiac glycosides and to regulate the G2/M cell phase. AMANTADIG treatment upregulated the expression of the pro-apoptotic survivin-2B variant in Caki-1 and 786-O cells. Moreover, treatment with AMANTADIG resulted in significantly lower survivin protein expression compared to 786-O control cells. Summarizing, treatment with all cardiac glycosides induced G2/M cell cycle arrest and downregulated the miR-2278 and miR-670-5p in microarray analysis. All cardiac glycosides affected the MAPK-pathway and survivin expression, both associated with the G2/M phase. Because cells in the G2/M phase are radio- and chemotherapy sensitive, cardiac glycosides like AMANTADIG could potentially improve the efficacy of radio- and/or chemotherapy in RCCs.
Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Digitoxigenin; Female; G2 Phase Cell Cycle Checkpoints; Humans; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; M Phase Cell Cycle Checkpoints; MicroRNAs; Signal Transduction; Survivin
PubMed: 28099931
DOI: 10.18632/oncotarget.14644 -
Annals of the American Thoracic Society Feb 2017Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly neutrophilic and complicates airway clearance therapies through cellular debris; excessive DNA; excessive and viscous mucus; and high concentrations of neutrophils, IL-8, and related cytokines liberated along the nuclear factor-κB signaling pathway.
OBJECTIVES
We conducted a preliminary, single-site, randomized, double-blind, placebo-controlled study to evaluate the effects over 28 days of two dose levels (0.05 mg and 0.1 mg daily) of an older cardiac glycoside, digitoxin, as compared with placebo, on safety, pharmacokinetics, and inflammatory markers in induced sputum obtained from 24 subjects with mild to moderate CF lung disease.
METHODS
Patients with CF 18-45 years old with any genotype combination were eligible. The primary objective was to measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum. Secondary objectives were to measure (1) the pharmacokinetics of digitoxin in sera of patients with stable CF; (2) safety indices, including ECG changes and sputum microbiology; (3) the effect of digitoxin on gene expression in nasal epithelial cells of patients with stable CF; and (4) quality-of-life scores using the Cystic Fibrosis Questionnaire-Revised.
MEASUREMENTS AND MAIN RESULTS
It took several weeks to achieve a therapeutic serum level of digitoxin in subjects with CF. No safety concerns emerged during the study. Digitoxin treatment showed a trend toward reduction in sputum free neutrophil elastase and neutrophil counts, but not a reduction in sputum IL-8. Digitoxin treatment did not reach statistical significance for the primary or secondary outcome measures over the 28-day study period. However, the nasal mRNA from the group receiving 0.1 mg of digitoxin daily had a distinct distribution of global gene expression levels as compared with either the 0.05-mg dose or placebo treatment. The mRNAs encoding chemokine/cytokine or cell surface receptors in immune cells were decreased in nasal epithelial cells at the higher dose, leading to pathway-mediated reductions in IL-8, IL-6, lung epithelial inflammation, neutrophil recruitment, and mucus hypersecretion.
CONCLUSIONS
At a dose of 0.1 mg daily for 28 days, digitoxin was safe for adults with CF lung disease, but it did not achieve a significant decrease in sputum inflammatory markers. Clinical trial registered with www.clinicaltrials.gov (NCT00782288).
Topics: Adolescent; Adult; Anti-Inflammatory Agents; Biomarkers; Cystic Fibrosis; Digitoxin; Double-Blind Method; Female; Humans; Inflammation; Interleukin-8; Leukocyte Count; Lung; Male; Maryland; Neutrophils; Sputum; Young Adult
PubMed: 28006108
DOI: 10.1513/AnnalsATS.201608-649OC -
BMJ Case Reports Dec 2016A previously well woman aged 63 years presents to the emergency department with vomiting, palpitations and 3 presyncopal episodes. She had no previous medical or cardiac...
A previously well woman aged 63 years presents to the emergency department with vomiting, palpitations and 3 presyncopal episodes. She had no previous medical or cardiac history, with the patient stating that she tried a herbal remedy of boiled comfrey leaves for insomnia 18 hours before arrival to the department. Her ECG showed multiple abnormalities, including bradycardia, second-degree atrioventricular node block, Mobitz Type 2, a shortened QT interval, downsloping ST depression and presence of U waves. After viewing the images of comfrey and foxglove, it highlighted the possibility of mistaken ingestion of Digitalis, containing the organic forms of cardiac glycosides, such as digoxin and digitoxin. Raised serum digoxin levels confirmed this. The patient was haemodynamically stable, and given digoxin-binding antibodies. After 5 days of cardiac monitoring, her ECG returned to normal rhythm, and she was discharged home.
Topics: Accidents; Antibodies, Heterophile; Atrioventricular Block; Bradycardia; Comfrey; Digitalis; Digoxin; Electrocardiography; Female; Humans; Middle Aged; Plant Leaves; Plant Poisoning; Plants, Medicinal; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Vomiting
PubMed: 27908913
DOI: 10.1136/bcr-2016-216995 -
Journal of Virology Feb 2017The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome potentially makes it vulnerable to modulators of RNA splicing,...
UNLABELLED
The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yields of four human adenoviruses (HAdV-A31, -B35, and -C5 and a species D conjunctivitis isolate) by at least 2 to 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein hexon is compromised. Quantitative reverse transcription-PCR (qRT-PCR) analyses revealed that both drugs altered E1A RNA splicing (favoring the production of 13S over 12S RNA) early in infection and partially blocked the transition from 12S and 13S to 9S RNA at late stages of virus replication. Expression of multiple late viral protein mRNAs was lost in the presence of either drug, consistent with the observed block in viral DNA replication. The antiviral effect was dependent on the continued presence of the drug and was rapidly reversible. RIDK34, a derivative of convallotoxin, although having more potent antiviral activity, did not show an improved selectivity index. All three drugs reduced metabolic activity to some degree without evidence of cell death. By blocking adenovirus replication at one or more steps beyond the onset of E1A expression and prior to genome replication, digoxin and digitoxin show potential as antiviral agents for treatment of serious adenovirus infections. Furthermore, understanding the mechanism(s) by which digoxin and digitoxin inhibit adenovirus replication will guide the development of novel antiviral therapies.
IMPORTANCE
Despite human adenoviruses being a common and, in some instances, life-threating pathogen in humans, there are few well-tolerated therapies. In this report, we demonstrate that two cardiotonic steroids already in use in humans, digoxin and digitoxin, are potent inhibitors of multiple adenovirus species. A synthetic derivative of the cardiotonic steroid convallotoxin was even more potent than digoxin and digitoxin when tested with HAdV-C5. These drugs alter the cascade of adenovirus gene expression, acting after initiation of early gene expression to block viral DNA replication and synthesis of viral structural proteins. These findings validate a novel approach to treating adenovirus infections through the modulation of host cell processes.
Topics: Adenoviridae; Antiviral Agents; Cardiac Glycosides; Cell Line; DNA Replication; DNA, Viral; Digitoxin; Digoxin; Gene Expression Regulation, Viral; Humans; Virus Replication
PubMed: 27881644
DOI: 10.1128/JVI.01623-16 -
Tidsskrift For Den Norske Laegeforening... Nov 2016BACKGROUND In 2011, following a period with delivery problems, the only registered digitoxin drug in Norway was replaced with digoxin. As a result, approximately 21 000...
BACKGROUND In 2011, following a period with delivery problems, the only registered digitoxin drug in Norway was replaced with digoxin. As a result, approximately 21 000 patients had to replace digitoxin with digoxin. There are important pharmacokinetic differences between digitoxin and digoxin (the general term for both drugs is digitalis), which must be taken into account when changing therapy. The aim of this study was to investigate compliance of drug security, during the transition from digitoxin to digoxin in Norway.MATERIAL AND METHOD Enquiries addressed to the Norwegian Poison Information Centre and reports of fatal adverse effects to the Regional Drug Information Centres (RELIS) regarding intake of digitalis were analysed. Serum concentrations of digitoxin and digoxin analyzed at Oslo University Hospital were reviewed. All data sources were reviewed for the years 2010-2014 and patients > 20 years were included.RESULTS The total number of enquiries addressed to the Norwegian Poison Information Centre, fatal adverse drug reactions reported to RELIS, and patient samples in the toxic range analyzed at Oslo University Hospital increased from 2012, timewise related to the transition to digoxin.INTERPRETATION Despite extensive information from the Norwegian Medicines Agency, a small, transient increase was observed in the number of overdoses and reported deaths from digitalis related to change in therapy. The cause of the overdose was in many cases unknown. This study revealed several cases of incorrect dosage, simultaneous use of digitoxin and digoxin, and washout time that was insufficient or lacking before initiation of digoxin.
Topics: Aged; Aged, 80 and over; Digitoxin; Digoxin; Drug Overdose; Drug Substitution; Female; Guideline Adherence; Humans; Male; Norway; Poison Control Centers
PubMed: 27830905
DOI: 10.4045/tidsskr.15.0161 -
Tidsskrift For Den Norske Laegeforening... Nov 2016
Topics: Anti-Arrhythmia Agents; Digitoxin; Digoxin; Drug Substitution; Humans; Norway; Practice Guidelines as Topic
PubMed: 27830897
DOI: 10.4045/tidsskr.16.0810 -
Nature Communications Aug 2016New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human...
New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.
Topics: Animals; Cell Line, Tumor; Digitoxin; Drug Synergism; Enzyme Inhibitors; Female; Humans; Hydrogen-Ion Concentration; MAP Kinase Kinase 1; Male; Melanocytes; Melanoma; Mice; Mitochondria; Mutation; Phosphorylation; Primary Cell Culture; Protein Kinase Inhibitors; Signal Transduction; Skin; Skin Neoplasms; Sodium-Potassium-Exchanging ATPase; Xenograft Model Antitumor Assays
PubMed: 27545456
DOI: 10.1038/ncomms12336