digoxin and Brain-Neoplasms

Topics: Brain Neoplasms; Cell Line, Tumor; Digoxin; Glioblastoma; Humans; Oncolytic Viruses; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Zika Virus

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Digoxin; Drug Repositioning; Gene Expression Regulation, Neoplastic; Medulloblastoma; Mice, Inbred NOD; Mice, SCID; Mitochondria; Radiation, Ionizing; Signal Transduction; Survival Analysis; Systems Biology; Xenograft Model Antitumor Assays

Glioblastoma (GBM) is the most common brain tumor in adults and the mesenchymal GBM subtype was reported to be the most malignant, presenting severe hypoxia and necrosis. Here, we investigated the possible role of a hypoxic microenvironment for inducing a mesenchymal and invasive phenotype. The exposure of non-mesenchymal SNB75 and U87 cells to hypoxia induced a strong change in cell morphology that was accompanied by enhanced invasive capacity and the acquisition of mesenchymal marker expression. Further analyses showed the induction of HIF1α and HIF2α by hypoxia and exposure to digoxin, a cardiac glycoside known to inhibit HIF1/2 expression, was able to prevent hypoxia-induced mesenchymal transition. ShRNA-mediated knockdown of HIF1α, and not HIF2α, prevented this transition, as well as the knockdown of the EMT transcription factor ZEB1. We provide further evidence for a hypoxia-induced mesenchymal shift in GBM primary material by showing co-localization of GLUT1, ZEB1 and the mesenchymal marker YKL40 in hypoxic regions of the tumor. Collectively, our results identify a HIF1α-ZEB1 signaling axis that promotes hypoxia induced mesenchymal shift and invasion in GBM in a cell line dependent fashion.

Topics: Adipokines; Basic Helix-Loop-Helix Transcription Factors; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Shape; Chitinase-3-Like Protein 1; Digoxin; Epithelial-Mesenchymal Transition; Glioblastoma; Glucose Transporter Type 1; Homeodomain Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lectins; Necrosis; Neoplasm Invasiveness; Phenotype; RNA Interference; Signal Transduction; Transcription Factors; Transfection; Zinc Finger E-box-Binding Homeobox 1

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Topics: Animals; Antigens, CD; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cohort Studies; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ki-67 Antigen; Mice; Mice, SCID; Middle Aged; SOXB1 Transcription Factors; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation.. Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs).. These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.

Topics: Apoptosis; Brain Neoplasms; Calcium Channels; Cell Line, Tumor; Cell Proliferation; Digoxin; Glioblastoma; Humans; Male; Middle Aged; Mutation; Ouabain; Potassium Channels; Sodium Channels; Survival Analysis

The study assessed the isoprenoid pathway, digoxin synthesis, and neurotransmitter patterns in individuals of differing hemispheric dominance, neurogenetic disorders, and neoplasms. The HMG CoA reductase activity, serum digoxin, magnesium, tryptophan catabolites, tyrosine catabolites, and RBC membrane Na+-K+ ATPase activity were measured in individuals of differing hemispheric dominance. The digoxin status, membrane Na+-K+ ATPase activity, and serum magnesium were assessed in Huntington's disease, trisomy 21, glioblastoma multiforme, and non-Hodgkin's lymphoma (high grade lymphoma). The results showed that right hemispheric, chemically dominant individuals had elevated digoxin synthesis, increased tryptophan catabolites, and reduced tyrosine catabolites, and membrane Na+-K+ ATPase with hypomagnesemia. Left hemispheric, chemically dominant individuals had the opposite patterns. In neurogenetic disorders and neo plasms also hyperdigoxinemia induced membrane Na+-K+ ATPase inhibition, and hypomagnesemia similar to right hemispheric chemical dominance could be demonstrated. The role of hemispheric chemical dominance and hypothalamic digoxin secretion play a key role in the regulation of cell differentiation/proliferation and genomic function. Ninety-five percent of the patients with neurogenetic disorders and neoplasms were right-handed/left hemispheric dominant by dichotic listening test. However, all of them had biochemical patterns similar to right hemispheric chemical dominance. Hemispheric chemical dominance has no correlation to cerebral dominance detected by handness/dichotic listening test.

Topics: Adult; Brain; Brain Neoplasms; Cell Division; Cell Membrane; Cell Movement; Cell Transformation, Neoplastic; Digoxin; Down Syndrome; Functional Laterality; Genome, Human; Glioblastoma; Humans; Huntington Disease; Hydroxymethylglutaryl CoA Reductases; Lymphoma, Non-Hodgkin; Magnesium; Neurons; Ouabain

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glyco

Topics: Adult; Astrocytoma; Brain Neoplasms; Cholesterol; Digoxin; Dolichols; Erythrocyte Membrane; Female; Glycosaminoglycans; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Lymphoma, Non-Hodgkin; Male; Middle Aged; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Ubiquinone

Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway was studied in neurological and psychiatric disorders. The concentration of trytophan, quinolinic acid, kynurenic acid, serotonin and 5-hydroxyindoleacetic acid was found to be higher in the plasma of patients with all these disorders; while that of tyrosine, dopamine, epinephrine and norepinephrine was lower. There was increase in free fatty acids and decrease in albumin (factors modulating tryptophan transport) in the plasma of these patients. Concentration of digoxin, a modulator of amino acid transport, and the activity of HMG CoA reductase, which synthesizes digoxin, were higher in these patients; while RBC membrane Na+-K+ ATPase activity showed a decrease. Concentration of plasma ubiquinone (part of which is synthesised from tyrosine) and magnesium was also lower in these patients. No morphine could be detected in the plasma of these patients except in MS. On the other hand, strychnine and nicotine were detectable. These results indicate hypercatabolism of tryptophan and hypocatabolism of tyrosine in these disorders, which could be a consequence of the modulating effect of hypothalamic digoxin on amino acid transport.

Topics: Adult; Biogenic Monoamines; Brain Diseases; Brain Neoplasms; Digoxin; Epilepsy, Generalized; Erythrocytes; Fatty Acids, Nonesterified; Female; Glioma; Glycine Agents; Humans; Hydroxymethylglutaryl CoA Reductases; Kynurenic Acid; Magnesium; Male; Microvascular Angina; Middle Aged; Morphine; Narcotics; Nicotine; Nicotinic Agonists; Parkinson Disease; Quinolinic Acid; Schizophrenia; Serum Albumin; Sodium-Potassium-Exchanging ATPase; Strychnine; Tryptophan; Tyrosine; Ubiquinone

Subarachnoid haemorrhage is commonly associated with natriuresis and hyponatraemia. One possible explanation for these features is a defect in the central regulation of renal sodium reabsorption with increased secretion of a natriuretic factor. We investigated whether excess sodium secretion in patients with subarachnoid haemorrhage is related to increased secretion of natriuretic peptides or to the presence of digoxin-like immunoreactive substances.. We measured the plasma concentrations of digoxin-like immunoreactive substances (by a fluorescence polarisation immunoassay) and natriuretic peptides, aldosterone, renin, and antidiuretic hormone (by radioimmunoassay) in ten patients with aneurysmal subarachnoid haemorrhage, ten patients undergoing elective craniotomy for cerebral tumours, and 40 healthy controls of similar age and sex distribution. Samples were collected before surgery, 1 h, 4 h, and 12 h after surgery, then daily until 7 days postoperatively in the two groups of patients.. All patients with subarachnoid haemorrhage, but none of the tumour patients, showed increased urine output and urinary excretion of sodium (p = 0.018 for comparison of means of curves to 7 days). The patients with subarachnoid haemorrhage had much higher plasma concentrations of brain natriuretic peptide (BNP) than controls, on admission (mean 15.1 [SE 3.8] vs 1.6 [1.0] pmol/L, p < 0.001) and throughout the study period, accompanied by lower than normal aldosterone concentrations and normal plasma concentrations of atrial and C-type natriuretic peptides (ANP, CNP). The patients with tumours had similar plasma concentrations of ANP, BNP, and CNP to the controls. We did not detect digoxin-like immunoreactive substances in either group of patients.. Salt-wasting of central origin may induce hyponatraemia in patients with aneurysmal subarachnoid haemorrhage, possibly as a result of increased secretion of BNP with subsequent suppression of aldosterone synthesis.

Topics: Brain Neoplasms; Cardenolides; Digoxin; Enzyme Inhibitors; Female; Fluorescence Polarization Immunoassay; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Natriuretic Agents; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Subarachnoid Hemorrhage

Topics: Alcoholism; Brain Neoplasms; Digoxin; Evaluation Studies as Topic; False Negative Reactions; False Positive Reactions; Humans; Hypertension, Renal; Iodine Radioisotopes; Lung Diseases; Mammography; Mass Screening; Models, Theoretical; Pelvimetry; Prognosis; Radionuclide Imaging