piperidines and Glioblastoma

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Drug Delivery Systems; Glioblastoma; Mice; Pericytes; Piperidines; Pyrazoles; Pyrimidines; Tumor Microenvironment; Xenograft Model Antitumor Assays

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; 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Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cohort Studies; Disease-Free Survival; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Quinazolines; Sirolimus

Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM).. We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis.. The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75).. The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Male; Middle Aged; Piperidines; Quinazolines; Temozolomide; Treatment Outcome

Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma.. The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6).. Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths.. These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Pyridines; Supratentorial Neoplasms; Temozolomide

Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ).. A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs.. Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT.. Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Diverticulitis; Drug Administration Schedule; ErbB Receptors; Female; Gastrointestinal Hemorrhage; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Piperidines; Quinazolines; Temozolomide; Thrombocytopenia; Vascular Endothelial Growth Factor Receptor-2

Glioblastoma is a highly malignant and invasive brain tumor, and there is an urgent need to establish a treatment option that prevents its growth and metastasis. Blonanserin is an antipsychotic drug widely used in the treatment of schizophrenia. It has recently been reported to inhibit the growth of breast cancer cells. In this study, we investigated the effect of blonanserin on the proliferation and migration of glioblastoma cells. The anti-proliferative activity of blonanserin was evaluated in terms of cell viability, competition, and cell death pathways in glioblastoma. Cell viability studies showed that blonanserin had growth inhibitory ability regardless of the malignancy of glioblastoma cells, but at concentrations close to its IC

Topics: Antipsychotic Agents; Cell Proliferation; Glioblastoma; Humans; Piperidines

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis. The GBM microenvironment is highly heterogeneous and is composed of many cell types including astrocytes and endothelial cells (ECs) along with tumor cells, which are responsible for heightened resistance to standard chemotherapeutic drugs such as Temozolomide (TMZ). Here, we investigated how drug treatments impact stemness marker expression of GBM cells in multicellular tumor spheroid (MCTS) models. Co- and tri-culture MCTS constructed using U87-MG GBM cells, astrocytes, and/or ECs were cultured for 7 days. At Day 7, 5 μM lonafarnib (LNF), 100 μM TMZ, or combination of 5 μM LNF + 100 μM TMZ was added and the MCTS were cultured for an additional 48 h. We assessed the spheroid sizes and expression of stemness markers- NESTIN, SOX2, CD133, NANOG, and OCT4- through qRT-PCR and immunostaining. Following 48 h treatment with LNF, TMZ or their combination (LNF + TMZ), the spheroid sizes decreased compared to the untreated control. We also observed that the expression of most of the stemness markers significantly increased in the LNF + TMZ treated condition as compared to the untreated condition. These results indicate that drug treatment can influence the stemness marker expression of GBM cells in MCTS models and these aspects must be considered while evaluating therapies. In future, by incorporating other relevant cell types, we can further our understanding of their crosstalk, eventually leading to the development of new therapeutic strategies.

Topics: Cell Line, Tumor; Dibenzocycloheptenes; Drug Resistance, Neoplasm; Endothelial Cells; Glioblastoma; Humans; Nestin; Piperidines; Pyridines; Spheroids, Cellular; Temozolomide; Tumor Microenvironment

Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.

Topics: Alkaloids; Benzodioxoles; Brain Neoplasms; Cell Line, Tumor; Cytochrome P-450 Enzyme Inhibitors; Glioblastoma; Humans; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Survivin

In our study, our aim was to examine the cytotoxic and radio-sensitizing effect of the alkaloid piperine, a major pungent of black pepper, on two different human epithelial tumor cell lines in vitro. The growth of the human cell lines T98G (glioblastoma) and FaDu (hypopharyngeal carcinoma) was examined under the influence of piperine in different concentrations. In addition, after combined treatment with ionizing radiation, long-term survival was investigated with a colony formation assay. The proliferation was analyzed using the BrdU-assay, while the DNA repair capacity was examined via the γH2AX assay. Piperine reduced the growth of both cell lines in a concentration-dependent manner as well as a time-dependent one. After combined treatment with piperine and ionizing radiation, an inhibition of clonogenic survival could be proven. A reduced proliferation capacity and an additive effect on DNA damage 24 h after irradiation are possible causal mechanisms, which were also demonstrated for both cell lines. Based on the results presented in this study, piperine was shown to have cytotoxic antitumor activity and a radio-sensitizing effect in micromolar concentrations in the human tumor cells that were tested. Based on these results piperine represents a potential therapeutic option in radio-oncological treatment.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Hypopharynx; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Radiation Tolerance

Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-β signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-β signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-β and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-β receptor kinase inhibitor galunisertib, the JAK/STAT inhibitors AG490 and tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation, suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.

Topics: Brain Neoplasms; Catechin; Cell Line, Tumor; Concanavalin A; Epithelial-Mesenchymal Transition; Fibronectins; Glioblastoma; Humans; Matrix Metalloproteinase 14; Piperidines; Pyrazoles; Pyrimidines; Quinolines; Receptors, Transforming Growth Factor beta; Signal Transduction; Snail Family Transcription Factors; STAT3 Transcription Factor; Transforming Growth Factor beta1; Tyrphostins

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Sulfones; Temozolomide; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Animals; Brain Neoplasms; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Calcium-Binding Proteins; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Female; Glioblastoma; HeLa Cells; Humans; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; NFATC Transcription Factors; Piperidines; Urea; Xenograft Model Antitumor Assays

Cytoprotective agents are mainly used to protect the gastrointestinal tract linings and in the treatment of gastric ulcers. These agents are devoid of appreciable cytotoxic or cytostatic effects, and medicinal chemistry efforts to modify them into anticancer agents are rare. A drug repurposing campaign initiated in our laboratory with the primary focus of discovering brain cancer drugs resulted in drug-dye conjugate 1, a combination of the cytoprotective agent troxipide and heptamethine cyanine dye MHI 148. The drug-dye conjugate 1 was evaluated in three different patient-derived adult glioblastoma cell lines, commercially available U87 glioblastoma, and one paediatric glioblastoma cell line. In all cases, the conjugate 1 showed potent cytotoxic activity with nanomolar potency (EC

Topics: Antineoplastic Agents; Brain Neoplasms; Carbocyanines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; Drug Repositioning; Drug Therapy, Combination; Glioblastoma; Humans; Indoles; Molecular Structure; Piperidines; Temozolomide

Anaplastic lymphoma kinase (ALK) is expressed in ~ 60% of glioblastomas and conveys tumorigenic functions. Therefore, ALK inhibitory strategies with alectinib are conceivable for patients with glioblastoma. The aims of this preclinical study were to investigate efficacy as well as to understand and potentially overcome primary and acquired resistance mechanisms of alectinib in glioblastoma.. Efficacy of alectinib was analyzed dependent on ALK expression in different glioblastoma initiating cells and after lentiviral knockdown of ALK. Alectinib resistant cells were generated by continuous treatment with increasing alectinib doses over 3 months. M-RNA, phospho-protein and protein regulation were analyzed to decipher relevant pathways associated to treatment or resistance and specifically inhibited to evaluate rational salvage therapies.. Alectinib reduced clonogenicity and proliferation and induced apoptosis in ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. High expression of cMyc and activation of the ERK1/2 pathway conferred resistance against alectinib in ALK expressing glioblastoma cells. Pharmacological inhibition of these pathways by cMyc inhibitor or MEK inhibitor, trametinib, overcame alectinib resistance and re-sensitized resistant cells to continued alectinib treatment. The combination of alectinib with radiotherapy demonstrated synergistic effects in inhibition of clonogenicity in non-resistant and alectinib resistant glioblastoma cells.. The data offer rationales for alectinib treatment in ALK expressing glioblastoma and for the use of ALK expression status as potential biomarker for alectinib treatment. In addition, the results propose MEK inhibition or radiotherapy as reasonable salvage treatments after acquired alectinib resistance.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Biomarkers, Tumor; Carbazoles; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Tumor Cells, Cultured

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (

Topics: Animals; Autoradiography; Benzofurans; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Fluorine Radioisotopes; Glioblastoma; Humans; Magnetic Resonance Imaging; Mice; Mice, Knockout; Mice, Nude; Molecular Imaging; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, sigma; Sigma-1 Receptor; Transplantation, Heterologous

Salinomycin, an ionophore antibiotic, is known to be an effective agent in reducing the viability of Glioblastoma (GBM) cells. The combination of salinomycin with other chemotherapeutic drugs would help to overcome the drug resistance of GBM cells.. This study aims to test the combinatorial effect of salinomycin and AZD3463 in T98G GBM cells.. The cytotoxic effects of drugs on T98G GBM cells were determined by using WST-8 assay. Flow cytometry was used to identify apoptosis and cell cycle profiles after treatments. Real-time PCR was used to portray mRNA expression profiles of genes in the Wnt-signaling pathway after treatments.. IC50 concentrations of AZD3463 and salinomycin were 529nM and 7.3μM for 48h, respectively. The combination concentrations of AZD3463 and salinomycin were 3.3μM and 333nM, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. AZD3463, salinomycin, and their combination induced apoptosis in 1.2, 1.4, and 3.2 folds, respectively. AZD3463 and the combination treatment induced the cell cycle arrest at the G1 phase. Salinomycin and AZD3463 treatments, either alone or in combination, resulted in the downregulation or upregulation of mRNA expression levels of genes in the Wntsignaling pathway.. Salinomycin, AZD3463, and their combination may inhibit proliferation and induce apoptosis in GBM cells due to a decrease in expression levels of genes acting in both the canonical and non-canonical Wnt signaling pathways. The Wnt signaling pathway may be involved in salinomycin-AZD3463 drug interaction.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Glioblastoma; Humans; Indoles; Molecular Structure; Piperidines; Pyrans; Pyrimidines; Structure-Activity Relationship; Tumor Cells, Cultured

The endocannabinoid system has been associated with antiproliferative effects in several types of tumors through cannabinoid receptor-mediated cell death mechanisms. Oleamide (ODA) is a CB1/CB2 agonist associated with cell growth and migration by adhesion and/or ionic signals associated with Gap junctions. Antiproliferative mechanisms related to ODA remain unknown. In this work, we evaluated the effects of ODA on cell viability and morphological changes in a rat RG2 glioblastoma cell line and compared these effects with primary astrocyte cultures from 8-day postnatal rats. RG2 and primary astrocyte cultures were treated with ODA at increasing concentrations (25, 50, 100, and 200 μM) for different periods of time (12, 24, and 48 h). Changes in RG2 cell viability and morphology induced by ODA were assessed by viability/mitochondrial activity test and phase contrast microscopy, respectively. The ratios of necrotic and apoptotic cell death, and cell cycle alterations, were evaluated by flow cytometry. The roles of CB1 and CB2 receptors on ODA-induced changes were explored with specific receptor antagonists. ODA (100 μM) induced somatic damage, detachment of somatic bodies, cytoplasmic polarization, and somatic shrinkage in RG2 cells at 24 and 48 h. In contrast, primary astrocytes treated at the same ODA concentrations exhibited cell aggregation but not cell damage. ODA (100 μM) increased apoptotic cell death and cell arrest in the G1 phase at 24 h in the RG2 line. The effects induced by ODA on cell viability of RG2 cells were independent of CB1 and CB2 receptors or changes in intracellular calcium transient. Results of this novel study suggest that ODA exerts specific antiproliferative effects on RG2 glioblastoma cells through unconventional apoptotic mechanisms not involving canonical signals.

Topics: Animals; Cell Death; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glioblastoma; Hypnotics and Sedatives; Oleic Acids; Piperidines; Pyrazoles; Rats; Rats, Inbred F344; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD

Topics: Acrylamides; Animals; Autophagy; B7-H1 Antigen; Brain Neoplasms; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Movement; Cyanides; Cytokines; Delayed-Action Preparations; Drug Carriers; Glioblastoma; Guanidines; Humans; Injections, Intralesional; Macrophages; Membrane Proteins; Mice; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Polymers; RNA, Messenger; Signal Transduction; Tumor Microenvironment; Up-Regulation

Glioblastoma (GBM) is one of the major causes of brain cancer-related mortality worldwide. Temozolomide (TMZ) is an important agent against GBM. Acquired TMZ-resistance severely limits the chemotherapeutic effect and leads to poor GBM patient survival. To study the underlying mechanism of drug resistance, two TMZ resistant GBM cell lines, A172 and U87, were generated. In this study, the TMZ resistant cells have less apoptosis and cell-cycle change in response to the TMZ treatment. Western blot results revealed that cyclin E1 was upregulation in TMZ resistant cells. Inhibition or depletion of cyclin E1 re-sensitized the resistant cells to the TMZ treatment, which indicated the induction of cyclin E1 is the cause of TMZ resistance in GBM cells. Furthermore, we also found the expression of cyclin E1 stabilized the expression of Mcl-1, which contributes to the TMZ resistance in GBM cells. Finally, our in vivo xenograft data showed that the combination of flavopiridol, a cyclin E1/CDK2 inhibitor, overcomes the TMZ resistant by inducing higher apoptosis. Overall, our data provided a rationale to overcome the TMZ resistant in GBM treatment by inhibiting the cyclin E1 activity.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin E; Drug Resistance, Neoplasm; Female; Flavonoids; Glioblastoma; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Oncogene Proteins; Piperidines; Protein Kinase Inhibitors; Temozolomide; Transplantation, Heterologous

Glioblastoma (GBM) is the most malignant primary brain tumor, with dismal median survival. Treatment of GBM is particularly challenging given the intrinsic resistance to chemotherapy and difficulty of drugs to reach the tumor beds due to the blood-brain barrier. Here, we examined the efficacy of SHP099, a potent, selective, and oral SHP-2 inhibitor for treating GBM with activated platelet derived growth factor receptor alpha (PDGFRα) signaling.. The effects of SHP099 on cell survival of neural progenitor cells (NPCs), GBM cell lines, and patient-derived glioma stem-like cells (GSCs) were evaluated. Brain and plasma pharmacokinetics of SHP099 and its ability to inhibit SHP-2 signaling were assessed. SHP099 efficacy as a single agent or in combination with temozolomide (TMZ) was assessed using transformed mouse astrocyte and GSC orthotopic xenograft models.. Activated PDGFRα signaling in established GBM cells, GSCs, and transformed mouse astrocytes was significantly inhibited by SHP099 compared with NPCs in vitro and in vivo through targeting SHP-2-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 in GBM. SHP099 treatment specifically inhibited expression of JUN, a downstream effector of PDGFR signaling, thereby attenuating cell cycle progression in GBM cells with activated PDGFRα. Moreover, SHP099 accumulated at efficacious concentrations in the brain and effectively inhibited orthotopic GBM tumor xenograft growth. SHP099 exhibited antitumor activity either as a single agent or in combination with TMZ and provided significant survival benefits for GBM tumor xenograft-bearing animals.. Our data demonstrate the utility and feasibility of SHP099 as a potential therapeutic option for improving the clinical treatment of GBM in combination with TMZ.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Female; Glioblastoma; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood-brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Single drugs are marginally effective or even counterproductive. Common copy number alterations (PTEN loss, EGFR amplification, and NF1 loss) have a negligible correlation with single-drug or combination efficacy, reinforcing the importance of postgenetic approaches that account for kinase inhibitor promiscuity to match drugs to patients. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy. Although we focus on GBM, the approach is generally applicable.

Topics: Adenine; Anilides; Aniline Compounds; Antineoplastic Agents; Apoptosis; Blood-Brain Barrier; Cell Cycle; Cell Proliferation; Central Nervous System Neoplasms; Clinical Trials as Topic; Computer Simulation; Drug Discovery; Drug Therapy, Combination; Genomics; Glioblastoma; Humans; Models, Theoretical; Nitriles; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Quinolines; RNA, Messenger; Stochastic Processes; Transcriptome

Topics: Adult; Diacylglycerol Kinase; Glioblastoma; Humans; Piperidines; Ritanserin

Poly (ADP-ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. Previous studies have demonstrated that sufficient brain penetration is a prerequisite for efficacy of PARP inhibitors in glioma mouse models. Unfortunately, however, most of the PARP inhibitors developed to date have a limited brain penetration due to the presence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at the blood-brain barrier. AZD2461 is a novel PARP inhibitor that is unaffected by P-gp mediated resistance in breast cancer models and thus appears to have promising characteristics for brain penetration. We here use a comprehensive set of in vitro and in vivo models to study the brain penetration and oral bioavailability of AZD2461. We report that AZD2461 has a good membrane permeability. However, it is a substrate of P-gp and BCRP, and P-gp in particular limits its brain penetration in vivo. We show that AZD2461 has a low oral bioavailability, although it is not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Blood-Brain Barrier; Brain Neoplasms; Dogs; Drug Screening Assays, Antitumor; Glioblastoma; Madin Darby Canine Kidney Cells; Mice; Mice, Knockout; Neoplasm Proteins; Permeability; Phthalazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 μM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.

Topics: Adenosine Triphosphate; Brain Neoplasms; Caspase 3; Caspase 7; Cell Death; Cell Line, Tumor; Cymenes; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Monoterpenes; Piperidines; Protein Serine-Threonine Kinases; Quinolines; TRPM Cation Channels

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

Topics: Animals; Carbamates; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Glioblastoma; Humans; Mice; Mice, Inbred C57BL; Piperidines; Structure-Activity Relationship; Tumor Cells, Cultured

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.. Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo.. Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo.. Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.

Topics: Adenine; Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes.. Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels.. hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136).. Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Proliferation; Disease Models, Animal; Ether-A-Go-Go Potassium Channels; Gene Expression; Glioblastoma; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Molecular Targeted Therapy; Piperidines; Pyridines; Spheroids, Cellular; Tissue Array Analysis; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.

Topics: Apoptosis; Benzimidazoles; Brain Neoplasms; Carbamates; Cell Differentiation; Cell Proliferation; Dipeptides; ErbB Receptors; Glioblastoma; Humans; Microtubule-Associated Proteins; Neoplasm Invasiveness; Neoplastic Stem Cells; Phosphorylation; Piperidines; Receptor, Notch1; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Transcription Factor HES-1; Tumor Suppressor Proteins

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Death; Cell Line, Tumor; Glioblastoma; Humans; Mice; Models, Molecular; Piperidines; Quinolines; Stereoisomerism; Zebrafish

Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 

Topics: Acrylamides; Anthracenes; Apoptosis; Caspases; Cell Line, Tumor; Cell Survival; Cytokines; Dacarbazine; Drug Synergism; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 8; Nicotinamide Phosphoribosyltransferase; Piperidines; Reactive Oxygen Species; Signal Transduction; Temozolomide; Tocopherols

The failure of standard treatment for patients diagnosed with glioblastoma (GBM) coupled with the highly vascularized nature of this solid tumor has led to the consideration of agents targeting VEGF or VEGFRs, as alternative therapeutic strategies for this disease. Despite modest achievements in survival obtained with such treatments, failure to maintain an enduring survival benefit and more invasive relapsing tumors are evident. Our study suggests a potential mechanism by which anti-VEGF/VEGFR therapies regulate the enhanced invasive phenotype through a pathway that involves TGFβR and CXCR4. VEGFR signaling inhibitors (Cediranib and Vandetanib) elevated the expression of CXCR4 in VEGFR-expressing GBM cell lines and tumors, and enhanced the in vitro migration of these lines toward CXCL12. The combination of VEGFR inhibitor and CXCR4 antagonist provided a greater survival benefit to tumor-bearing animals. The upregulation of CXCR4 by VEGFR inhibitors was dependent on TGFβ/TGFβR, but not HGF/MET, signaling activity, suggesting a mechanism of crosstalk among VEGF/VEGFR, TGFβ/TGFβR, and CXCL12/CXCR4 pathways in the malignant phenotype of recurrent tumors after anti-VEGF/VEGFR therapies. Thus, the combination of VEGFR, CXCR4, and TGFβR inhibitors could provide an alternative strategy to halt GBM progression.

Topics: Adult; Aged; Angiogenesis Inhibitors; Animals; Benzylamines; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cyclams; Female; Glioblastoma; Heterocyclic Compounds; Humans; Interleukin-2 Receptor alpha Subunit; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptor Cross-Talk; Receptors, CXCR4; Receptors, Transforming Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Time Factors; Up-Regulation; Xenograft Model Antitumor Assays

APO866 is a potent inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), and inhibits nicotinamide adenine dinucleotide (NAD) synthesis. Our previous study showed that APO866 inhibits the proliferation of C6 glioblastoma cells, but failed to induce apoptosis. Since APO866 inhibits cellular metabolism and such metabolic stress is closely related with autophagy, thus we determined whether APO866 can induce autophagy in C6 glioblastoma cells and whether the autophagy induced by APO866 is pro-death or pro-survival. Using LC3 immunofluorescence imaging and transmission electron microscopy detection, we found that APO866 at 1-100 nM induced autophagy in C6 glioblastoma cells. APO866 at 1 nM mainly induced initial autophagic vacuoles. Whereas APO866 at 100 nM induced degrading autophagic vacuoles, as well as induced nuclei malformation and mitochondria swelling. In addition, APO866 concentration-dependently decreased the cell viability of C6 glioblastoma cells, and this effect was attenuated by autophagy inhibitors, including 3-methyladenine and LY294002. APO866 concentration-dependently decreased intracellular NAD level. Interestingly, APO866 at 1 nM slightly decreased intracellular NAD level, but dramatically increased autophagy-positive cells. The dramatical cell viability decreasing required the decreasing of intracellular NAD level to a very low threshold. Thus, our results indicated that APO866 induced pro-death autophagy in C6 glioblastoma cells by decreasing intracellular NAD, and low concentration of APO866 can be used as an autophagy inducer in autophagic-death sensitive glioblastoma.

Topics: Acrylamides; Animals; Autophagy; Cell Death; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Glioblastoma; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Rats; Vacuoles

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.

Topics: Animals; Brain Neoplasms; Cell Death; Glioblastoma; Heterografts; Humans; Hydroxyquinolines; MAP Kinase Kinase 4; Mice; Neoplasm Transplantation; Pinocytosis; Piperidines; Quinolines; Small Molecule Libraries; Vacuoles; Zebrafish

Attempts to treat cancer with drugs that target mutated proteins have met with mixed success. By screening for compounds that alter the phenotype of glioblastoma cells-an aggressive brain tumor-Kitambi et al. identify a potential new treatment of the disease and shed light on an unusual cell death mechanism.

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

In a recent Cell paper, Kitambi and colleagues identify a small molecule (Vacquinol-1) that has beneficial effects on a glioblastoma multiforme mouse model by oral administration. In glioblastoma cells, Vacquinol-1 targets macropinocytosis, a cellular process that will not lead to cell death in normal cells.

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

Topics: Acetaminophen; Analgesics, Opioid; Anti-Inflammatory Agents; Anticonvulsants; Antiemetics; Antineoplastic Agents; Dacarbazine; Dexamethasone; Drug Combinations; Erythema; gamma-Globulins; Glioblastoma; Humans; Immunologic Factors; Levetiracetam; Male; Methylprednisolone; Middle Aged; Omeprazole; Oxycodone; Piperidines; Piracetam; Proton Pump Inhibitors; Quinazolines; Stevens-Johnson Syndrome; Temozolomide; Wound Healing

Several previous reports have established the Pentax Airwayscope (Pentax AWS, S-100, HOYA-PENTAX, Tokyo, Japan) as an efficient tool for tracheal intubation in adult patients. The Pentax AWS is often successfully used with an INTLOCK blade; to date, however, INTLOCK blades have been released for neonatal and pediatric patients only. In this case, we performed tracheal intubation using a Pentax AWS attached to a pediatric-type INTLOCK blade (ITL-P) in an adult patient fitted with a Leksell Stereotactic frame (Elekta, Sweden). The patient weighed 45 kg and was 154 cm tall, and was scheduled for a tumor biopsy due to glioblastoma in the brain stem. The patient was preoperatively fitted with a Leksell frame on her head. The patient was not premedicated and was monitored with electrocardiography (ECG), noninvasive blood pressure, and pulse oximetry. Following pre-oxygenation, general anesthesia was induced using propofol 4.0 microg x ml with target-controlled infusion and remifentanil 0.25 microg x kg(-1) hr(-1). After loss of consciousness, we administered 30-mg rocuronium boluses. We initially attempted tracheal intubation first using a Macintosh laryngoscope and then a Pentax AWS, but we could not achieve tracheal intubation with either of these instruments. Upon switching to a Pentax AWS with an ITL-P, we successfully achieved tracheal intubation without any complications. Anesthesia was maintained uneventfully with 3.0 microg x ml(-1) propofol and remifentanil 0.10 to 0.25 microg x kg(-1) x hr(-1) in oxygen and air. Further study is needed to facilitate the effective use of the Pentax AWS and the ITL-P in such cases.

Topics: Adult; Anesthesia, General; Brain Neoplasms; Brain Stem; Female; Glioblastoma; Humans; Intubation, Intratracheal; Laryngoscopes; Piperidines; Propofol; Remifentanil

Although diacylglycerol kinase α (DGKα) has been linked to several signaling pathways related to cancer cell biology, it has been neglected as a target for cancer therapy. The attenuation of DGKα activity via DGKα-targeting siRNA and small-molecule inhibitors R59022 and R59949 induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in noncancerous cells. We determined that mTOR and hypoxia-inducible factor-1α (HIF-1α) are key targets of DGKα inhibition, in addition to its regulation of other oncogenes. DGKα regulates mTOR transcription via a unique pathway involving cyclic AMP. Finally, we showed the efficacy of DGKα inhibition with short hairpin RNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer.

Topics: Apoptosis; Brain Neoplasms; Cell Line, Tumor; Diacylglycerol Kinase; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Targeted Therapy; Piperidines; Pyrimidinones; Quinazolinones; RNA, Small Interfering; Thiazoles

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Line, Tumor; Cell Survival; Drug Synergism; Female; Glioblastoma; Humans; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Prognosis; Protein Kinase Inhibitors; Quinazolines; Young Adult

Autophagy is a lysosomal degradation pathway that can provide energy through its recycling mechanism to act as a cytoprotective adaptive response mediating treatment resistance in cancer cells. We investigated the autophagy-inducing effects of ZD6474, a small-molecule inhibitor that blocks activities of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET tyrosine kinases.. We investigated the effects of ZD6474 on autophagy in glioblastomas cells. The ZD6474 mechanism of action was determined by western blot. We then examined the impacts of the inhibition of autophagy in combination with ZD6474 on cell apoptosis in vitro. Furthermore, we evaluated the synergistic anticancer activity of combination treatment with an autophagy inhibitor (chloroquine) and ZD6474 in U251 glioblastoma cells xenograft model.. ZD6474-induced autophagy was dependent on signalling through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. ZD6474-induced autophagy was inhibited by both knockdown of the ATG7 and Beclin 1 gene, essential autophagy genes, and pharmacologic agents (chloroquine and 3-methyalanine) treatment. Both treatments also dramatically sensitised glioblastoma cells to ZD6474-induced apoptosis, decreasing cell viability in vitro. Furthermore, in a xenograft mouse model, combined treatment with ZD6474 and chloroquine significantly inhibited U251 tumour growth, and increased the numbers of apoptotic cells compared with treatment with either agent alone.. Autophagy protects glioblastoma cells from the proapoptotic effects of ZD6474, which might contribute to tumour resistance against ZD6474 treatment.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 7; Beclin-1; Cell Line, Tumor; Cell Survival; Chloroquine; ErbB Receptors; Glioblastoma; Humans; Membrane Proteins; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin-Activating Enzymes; Xenograft Model Antitumor Assays

Poly(ADP-ribose) polymerases (PARPs) are recognized as key regulators of cell survival or death. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. The enzyme may be overactivated in response to inflammatory cues, thus depleting cellular energy pools and eventually causing cell death. Accordingly, PARP-1 inhibitors, acting by competing with its physiological substrate NAD(+), have been proposed to play a protective role in a wide range of inflammatory and ischemia/reperfusion-associated diseases. Recently, it has also been reported that PARP-1 regulates proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and enzymes (e.g., iNOS). Furthermore, PARP-1 has been shown to act as a coactivator of NF-κB- and other transcription factors implicated in stress/inflammation, as AP-1, Oct-1, SP-1, HIF, and Stat-1. To further substantiate this hypothesis, we tested the biomolecular effects of PARP-1 inhibitors DPQ and PJ-34 on human glioblastoma cells, induced to a proinflammatory state with lipopolysaccharide and Interferon-γ. PARP-1 expression was evaluated by laser scanning confocal microscopy immunofluorescence (LSM); nitrite production, LDH release and cell viability were also determined. LSM of A-172, SNB-19 and CAS-1 cells demonstrated that DPQ and PJ-34 downregulate PARP-1 expression; they also cause a decrease of LDH release and nitrite production, while increasing cell viability. Similar effects were caused in all three cell lines by N-mono-methyl-arginine, a well known iNOS inhibitor, and by L-carnosine and trehalose, two antioxidant molecules. These results demonstrate that, similar to other well characterized drugs, DPQ and PJ-34 reduce cell inflammation and damage that follow PARP-1 overexpression, while they increase cell survival: this suggests their potential exploitation in clinical Medicine.

Topics: Anti-Inflammatory Agents; Biomarkers; Brain Neoplasms; Carnosine; Cell Line, Tumor; Cell Survival; Coloring Agents; Down-Regulation; Fluorescent Antibody Technique; Glioblastoma; Humans; Isoquinolines; L-Lactate Dehydrogenase; Microscopy, Confocal; Nitrites; Phenanthrenes; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Tetrazolium Salts; Thiazoles; Trehalose

The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression.. Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers.. In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib.. EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a "personalized" approach to GBM management.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Line, Tumor; Chemoradiotherapy; Drug Administration Schedule; ErbB Receptors; Glioblastoma; Humans; Mice; Mice, Nude; Neoplasm Proteins; Piperidines; Quinazolines; Radiation Tolerance; Receptors, Vascular Endothelial Growth Factor; Tumor Burden; Xenograft Model Antitumor Assays

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in the salvaging pathway for the synthesis of nicotinamide adenine dinucleotide (NAD) that is involved in cell metabolism and proliferation. NAMPT is normally absent in astrocyte but highly expressed in glioblastoma, suggesting that it may promote cell survival through synthesizing more NAD. In this report, we evaluated the effect of APO866, a potent inhibitor of NAMPT against C6 glioblastoma. We found that APO866 inhibited the growth of C6 glioblastoma cells with IC(50) in nano-molar range. APO866 depleted intracellular NAD, caused marked inhibition of ERK activation and induced G2/M cell-cycle arrest. The effects by APO866 were abrogated by nicotinamide mononucleotide (NMN), the direct product of NAMPT. Administration of U0126, an ERK1/2 inhibitor, inhibited cell growth but displayed no synergistic effect with APO866. Taken together, our results indicated that APO866 is a potent growth inhibitor against glioblastoma through targeting NAMPT.

Topics: Acrylamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Intracellular Space; M Phase Cell Cycle Checkpoints; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Rats

Cdk9 and Cdk7 are cdc2-like serine/threonine kinases that stabilize RNA transcript elongation through RNA polII carboxyl terminal domain (CTD) phosphorylation and are considered suitable targets for cancer therapy. The effects of flavopiridol and of siRNA-mediated inhibition of Cdk9 and/or Cdk7 were analyzed in human glioblastoma and human prostate cancer cell lines. One finding revealed that Cdk9 and Cdk7 could substitute each other in RNA polII CTD phosphorylation in contrast to the in vitro system. Thus, a simultaneous inhibition of Cdk9 and Cdk7 might be required both for targeting malignant cells and developing a platform for microarray analysis. However, these two pathways are not redundant, as indicated by differential effects observed in cell cycle regulation following siRNA-mediated inhibition of Cdk9 and/or Cdk7 in human PC3 prostate cancer cell line. Specifically, siRNA-mediated inhibition of Cdk9 caused a shift from G 0/G 1 to G 2/M phase in human PC3 prostate cancer cell line. Another finding showed that flavopiridol treatment induced a substantial AKT-Ser473 phosphorylation in human glioblastoma T98G cell line in contrast to siRNA-mediated inhibition of Cdk9 and Cdk9 combined with Cdk7, whereas siRNA-mediated silencing of Cdk7 caused a minor increase in AKT-Ser473 phosphorylation. AKT-Ser473 is a hallmark of AKT pathway activation and may protect cells from apoptosis. This finding also shows that Cdk9 and Cdk7 pathways are not redundant and may have important implications in drug development and for studying the mechanism of chemoresistance in malignant cells.

Topics: Blotting, Western; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Drug Design; Enzyme Activation; Flavonoids; Gene Expression Regulation, Neoplastic; Gene Silencing; Glioblastoma; Humans; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; RNA Polymerase II; RNA, Small Interfering; Serine; Signal Transduction; Time Factors

Currently, clinically available options for treating glioblastoma (GBM) are quite limited, and there is a clear need to develop novel treatment strategies that can more effectively manage tumors. Here, we present a combination treatment of temozolomide (TMZ), a blood-brain barrier penetrating DNA alkylating agent, and ZD6474 (vandetanib), a VEGFR2 and EGFR dual-targeting anti-angiogenic agent, as a novel treatment strategy for GBM. In a U-87MG orthotopic xenograft model, the combination treatment provided a marked 94% tumor volume reduction. This reduction was greater than that achieved by monotherapy of either agent, and was correlated with a statistically significant reduction in microvessel density (CD31+ cells) and proliferation (PCNA+ cells). These results confirm the necessity to target angiogenesis in addition to utilizing cytotoxic approaches, and provide the rationale for application of TMZ + ZD6474 combination therapy for treating GBM patients in the clinical setting.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Dacarbazine; Drug Synergism; Glioblastoma; Humans; Male; Mice; Mice, Inbred BALB C; Microvessels; Piperidines; Quinazolines; Temozolomide; Tumor Burden; Xenograft Model Antitumor Assays

The Notch pathway is dysregulated and a potential target in glioblastoma multiforme (GBM). Currently available Notch inhibitors block γ-secretase, which is necessary for Notch processing. However, Notch is first cleaved by α-secretase outside the plasma membrane, via a disintegrin and metalloproteinase-10 and -17. In this work, we used a potent α-secretase inhibitor (ASI) to test inhibition of glioblastoma growth and inhibition of Notch and of both novel and known Notch targets. Featured in this study are luciferase reporter assays and immunoblot, microarray analysis, chromatin immunoprecipitation (ChIP), quantitative real-time PCR, cell number assay, bromodeoxyuridine incorporation, plasmid rescue, orthotopic xenograft model, and local delivery of treatment with convection-enhanced delivery using nanoparticles, as well as survival, MRI, and ex vivo luciferase assay. A CBF1-luciferase reporter assay as well as an immunoblot of endogenous Notch revealed Notch inhibition by the ASI. Microarray analysis, quantitative real-time PCR, and ChIP of ASI and γ-secretase inhibitor (GSI) treatment of GBM cells identified known Notch pathway targets, as well as novel Notch targets, including YKL-40 and leukemia inhibitory factor. Finally, we found that local nanoparticle delivery of ASIs but not GSIs increased survival time significantly in a GBM stem cell xenograft treatment model, and ASI treatment resulted in decreased tumor size and Notch activity. This work indicates α-secretase as an alternative to γ-secretase for inhibition of Notch in GBM and possibly other cancers as well, and it identifies novel Notch targets with biologic relevance and potential as biomarkers.

Topics: Amyloid Precursor Protein Secretases; Animals; Apoptosis; Biomarkers, Tumor; Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Proliferation; Chromatin Immunoprecipitation; Gene Expression Profiling; Glioblastoma; Humans; In Vitro Techniques; Luciferases; Magnetics; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, Notch; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spiro Compounds; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Glioblastoma multiforme (GBM) is a devastating brain tumor with poor prognosis and low median survival time. Standard treatment includes radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). However, a large percentage of tumors are resistant to the cytotoxic effects of the TMZ-induced DNA lesion O(6)-methylguanine due to elevated expression of the repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) or a defect in the mismatch repair (MMR) pathway. Although a majority of the TMZ-induced lesions (N7-methylguanine and N3-methyladenine) are base excision repair (BER) substrates, these DNA lesions are also readily repaired. However, blocking BER can enhance response to TMZ and therefore the BER pathway has emerged as an attractive target for reversing TMZ resistance. Our lab has recently reported that inhibition of BER leads to the accumulation of repair intermediates that induce energy depletion-mediated cell death via hyperactivation of poly(ADP-ribose) polymerase. On the basis of our observation that TMZ-induced cell death via BER inhibition is dependent on the availability of nicotinamide adenine dinucleotide (NAD(+)), we have hypothesized that combined BER and NAD(+) biosynthesis inhibition will increase TMZ efficacy in glioblastoma cell lines greater than BER inhibition alone. Importantly, we find that the combination of BER and NAD(+) biosynthesis inhibition significantly sensitizes glioma cells with elevated expression of MGMT and those deficient in MMR, two genotypes normally associated with TMZ resistance. Dual targeting of these two interacting pathways (DNA repair and NAD(+) biosynthesis) may prove to be an effective treatment combination for patients with resistant and recurrent GBM.

Topics: Acrylamides; Adenosine Triphosphate; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Dacarbazine; DNA Glycosylases; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Glioblastoma; Humans; Hydroxylamines; Immunoblotting; Methyl Methanesulfonate; NAD; Piperidines; Poly(ADP-ribose) Polymerases; RNA Interference; Temozolomide

We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs, combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gefitinib; Glioblastoma; Histone Deacetylase Inhibitors; Humans; Models, Biological; Phenylbutyrates; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptor Protein-Tyrosine Kinases; Tumor Stem Cell Assay

Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

Topics: Actins; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Benzamides; Calcium; Cell Line, Tumor; Cell Movement; Endoplasmic Reticulum; Female; Glioblastoma; Guanine Nucleotide Dissociation Inhibitors; Humans; Mice; Neoplasm Transplantation; Piperidines; Receptors, sigma; rho-Specific Guanine Nucleotide Dissociation Inhibitors; Transplantation, Heterologous

Endothelin-1 (ET-1), a vasoactive and mitogenic peptide mainly produced by vascular endothelial cells, may be involved in the progression of several human tumors. Here, we present an immunohistochemical analysis of the expression pattern of ET-1 receptor subtypes (ET(A)-R and ET(B)-R) and a functional study of their potential role in human oligodendrogliomas and oligoastrocytomas. By comparison, we assessed the corresponding expression patterns of glioblastomas. Interestingly, a nuclear localization of ET-1 receptor subtypes (associated or not with a cytoplasmic labeling) was constantly observed in tumor cells from all three glioma types. Moreover, we noted a distinct receptor distribution in the different gliomas: a nuclear expression of ET(B)-R by tumor cells was found to be restricted to oligodendrogliomas and oligoastrocytomas, while a nuclear expression of ET(A)-R was only detected in tumor cells from some glioblastomas. Using primary cultures of oligodendroglial tumor cells, we confirmed the selective expression of nuclear ET(B)-R, together with a plasma membrane expression, and further demonstrated that this receptor was functionally coupled to intracellular signaling pathways known to be involved in cell survival and/or proliferation: extracellular signal-regulated kinase and focal adhesion kinase activation, actin cytoskeleton reorganization. In addition, impairment of ET(B)-R activation in these cells by in vitro treatment with an ET(B)-R-specific antagonist induced cell death. These data point to ET-1 as a possible survival factor for oligodendrogliomas via ET(B)-R activation and suggest that ET(B)-R-specific antagonists might constitute a potential therapeutic alternative for oligodendrogliomas.

Topics: Actin Cytoskeleton; Antihypertensive Agents; Astrocytoma; Brain Neoplasms; Cell Membrane; Cell Nucleus; Cell Survival; Cytoplasm; Endothelin B Receptor Antagonists; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Glioblastoma; Humans; Immunohistochemistry; Oligodendroglioma; Oligopeptides; Piperidines; Protein-Tyrosine Kinases; Receptor, Endothelin A; Receptor, Endothelin B; Tumor Cells, Cultured

Glioblastoma multiforme is an aggressive disease in which vascular endothelial growth factor (VEGF) and the EGF receptor (EGFR) are implicated in tumor growth, relapse, and resistance to radiotherapy and chemotherapy. The VEGF receptors VEGFR-1 (flt-1) and VEGFR-2 (KDR), typically present on endothelial cells, have also been identified in human glioblastoma tissues and cell lines. In addition, EGFR is dysregulated in the majority of human glioblastomas and EGFR overexpression correlates with shorter survival. We have investigated the antitumor and antiangiogenic effect of ZD6474, an inhibitor of both VEGFR and EGFR signaling as a single agent and in combination with ionizing radiation.. We have used ZD6474 and/or ionizing radiation in human glioblastoma cell lines D54 and U251 in vitro and in nude mice bearing established xenografts. The effects of treatment on tumor blood vessels and protein expression were evaluated by Western blot and immunohistochemistry.. As single agents, ionizing radiation and ZD6474 caused a dose-dependent inhibition of soft agar growth in D54 and U251 cell lines, whereas a cooperative effect was obtained in combination. Treatment of mice bearing D54 xenografts with either ZD6474 or radiotherapy alone caused tumor growth inhibition that was reversible upon treatment cessation. A cooperative and long-lasting inhibition of tumor growth was obtained with ZD6474 in combination with concomitant radiotherapy. The antiproliferative effect was accompanied by inhibition of VEGF protein expression and inhibition of angiogenesis as measured by vessel counting.. This study shows the antitumor activity of ZD6474 in combination with ionizing radiation in glioblastoma both in vitro and in vivo, and provides a scientific rationale to evaluate ZD6474 alone or in combination with radiotherapy in patients affected by this disease.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Collagen; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Female; Glioblastoma; Humans; Immunohistochemistry; In Vitro Techniques; Laminin; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Piperidines; Proteoglycans; Quinazolines; Radiation, Ionizing; Time Factors; Vascular Endothelial Growth Factor A

Evidence has accumulated showing that vasoactive peptides, such as endothelin-1, adrenomedullin and urotensin-II, are expressed in various kinds of tumour cells. In the present study, the expression of endothelin-1 and endothelin receptors was studied in eight human tumour cell lines: T98G (glioblastoma), IMR-32 and NB69 (neuroblastoma), BeWo (choriocarcinoma), SW-13 (adrenocortical carcinoma), DLD-1 (colonic carcinoma), HeLa (cervical carcinoma) and VMRC-RCW (renal carcinoma). Reverse transcriptase-PCR showed expression of endothelin-1 mRNA in seven out of the eight cell lines, the exception being BeWo cells. ET(A) receptor mRNA was expressed in T98G, IMR-32 and NB69 cells, but weakly in the other cells. ET(B) receptor mRNA was expressed in IMR-32, NB69 and BeWo cells, but only weakly in T98G and HeLa cells. Immunoreactive endothelin was detected in the culture media of six out of the eight cell lines, but not in that of IMR-32 or BeWo cells. Treatment of T98G cells with an anti-endothelin-1 antibody or an anti-adrenomedullin antibody for 24 h decreased cell numbers to approx. 84% and 90% of control respectively. Treatment with the ET(A) receptor antagonist BQ-610 (1 microM) significantly decreased cell number to about 90% of control, whereas the ET(B) receptor antagonist BQ-788 had no significant effect. On the other hand, exogenously added endothelin-1, adrenomedullin or urotensin-II (0.1 microM) had no significant effects on cell number. These results suggest that endothelin-1 acts as a paracrine or autocrine growth stimulator in tumours. The effect of endothelin-1 on tumour growth appears to be mediated by the ET(A) receptor.

Topics: Adrenal Cortex Neoplasms; Adrenomedullin; Antibodies, Monoclonal; Cell Division; Choriocarcinoma; Colonic Neoplasms; Endothelin Receptor Antagonists; Endothelin-1; Glioblastoma; Growth Substances; HeLa Cells; Humans; Kidney Neoplasms; Neuroblastoma; Oligopeptides; Peptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Tumor Cells, Cultured; Urotensins; Vasodilator Agents

Previous studies have demonstrated that astrocytomas express elevated levels of activated Ras.GTP despite the absence of activating Ras mutations. Farnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Ras-mediated signaling. SCH66336 is a potent FTI presently undergoing clinical trials in patients with solid tumors. We evaluated the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice. SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC(50) ranging from 0.6 microM to 32.3 microM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth inhibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a combination of the H-, K-, and N-isotype-specific Ras.GTP levels. These data indicate that the absence of Ras mutations does not preclude chemotherapeutic efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras.GTP levels are a promising marker of drug efficacy.

Topics: Alkyl and Aryl Transferases; Animals; Astrocytoma; Brain Neoplasms; Cell Division; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Glioblastoma; Guanosine Triphosphate; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Monomeric GTP-Binding Proteins; Mutation; Piperidines; Pyridines; ras Proteins; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Ras activation occurs through stimulation of an upstream growth factor receptor such as epidermal growth factor receptor (EGFR). The ultimate effect of Ras is to induce nuclear transcription via a signaling pathway sequentially involving Raf, MAP kinase kinase (MEK), and mitogen-activated protein kinase (MAPK). To transform cells, Ras oncoproteins must be posttranslationally modified with a farnesyl group in a reaction catalyzed by farnesyl protein transferase. Farnesyltransferase inhibitors, therefore, have been proposed as potent anticancer agents. This study demonstrates the growth-inhibitory effects of farnesyltransferase inhibitor SCH66336 on human glioblastoma cell lines U-251 MG, U-251/E4 MG (a stably transfected cell line with elevated EGFR expression), and U-87 MG. As determined by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) and viability assays, the concentration required to achieve 50% inhibition (IC50) ranged from 30 microM (single 24-h treatment) to 10 microM (5-day treatment). U-251/E4 MG with overexpression of EGFR were more sensitive than U-251 MG parental cells. These observations were also supported by soft agar analysis. Cells treated with SCH66336 underwent G2 arrest. Western blot analysis revealed a decrease in phospho-MAPK levels upon treatment with 10 microM SCH66336, whereas MAPK levels were unaffected by the drug. Interestingly, increased expression of EGFR was observed in U-251 MG and U-251/E4 MG but not in U-87 MG in the presence of the inhibitor. These results demonstrate that SCH66336 inhibits viability and anchorage-independent growth in a time- and dose-dependent manner in glioblastoma cell lines U-251 MG, U-251/E4 MG, and U-87 MG via a signal transduction pathway involving the down-regulation of phospho-MAPK. Overexpression of EGFR appears to alter cellular sensitivity to farnesyltransferase inhibitors. This may have a particularly important implication in glioblastoma, where over 50% of tumors have amplification and overexpression of EGFR.

Topics: Alkyl and Aryl Transferases; Cell Division; Cell Survival; Enzyme Inhibitors; Farnesyltranstransferase; G2 Phase; Glioblastoma; Humans; Mitogen-Activated Protein Kinases; Piperidines; Pyridines; Tumor Cells, Cultured