Peignan L.,Austral University of Chile |
Garrido W.,Austral University of Chile |
Segura R.,Institute Neurocirugia Dr Asenjo |
Melo R.,Institute Neurocirugia Dr Asenjo |
And 4 more authors.
Neurochemical Research | Year: 2011
Glioblastoma multiforme (GBM) is a brain tumour characterised by a remarkably high chemoresistance and infiltrating capability. To date, chemotherapy with temozolomide has contributed only poorly to improved survival rates in patients. One of the most important mechanisms of chemoresistance comes about through the activity of certain proteins from the ATP-binding cassette superfamily that extrudes antitumour drugs, or their metabolites, from cells. We identify an increased expression of the multiple drug resistance-associated protein 1 (Mrp1) in glioblastoma multiforme biopsies and in T98G and G44 cell lines. The activity of this transporter was also confirmed by measuring the extrusion of the fluorescent substrate CFDA. The sensitivity of GBM cells was low upon exposure to temozolomide, vincristine and etoposide, with decreases in cell viability of below 20% seen at therapeutic concentrations of these drugs. However, combined exposure to vincristine or etoposide with an inhibitor of Mrp1 efficiently decreased cell viability by up to 80%. We conclude that chemosensitization of cells with inhibitors of Mrp1 activity might be an efficient tool for the treatment of human GBM. © 2011 Springer Science+Business Media, LLC.
Quezada C.,Austral University of Chile |
Garrido W.,Austral University of Chile |
Oyarzun C.,Austral University of Chile |
Fernandez K.,Diego Portales University |
And 5 more authors.
Journal of Cellular Physiology | Year: 2013
Glioblastoma multiforme (GBM) cells are characterised by their extreme chemoresistance. The activity of multiple-drug resistance (MDR) transporters that extrude antitumor drugs from cells plays the most important role in this phenomenon. To date, the mechanism controlling the expression and activity of MDR transporters is poorly understood. Activity of the enzyme ecto-5′-nucleotidase (CD73) in tumor cells, which hydrolyses AMP to adenosine, has been linked to immunosuppression and prometastatic effects in breast cancer and to the proliferation of glioma cells. In this study, we identify a high expression of CD73 in surgically resected samples of human GBM. In primary cultures of GBM, inhibition of CD73 activity or knocking down its expression by siRNA reversed the MDR phenotype and cell viability was decreased up to 60% on exposure to the antitumoral drug vincristine. This GBM chemosensitization was caused by a decrease in the expression and activity of the multiple drug associated protein 1 (Mrp1), the most important transporter conferring multiple drug resistance in these cells. Using pharmacological modulators, we have recognized the adenosine A3 receptor subtype in mediation of the chemoresistant phenotype in these cells. In conclusion, we have determined that the activity of CD73 to trigger adenosine signaling sustains chemoresistant phenotype in GBM cells. © 2012 Wiley Periodicals, Inc.
PubMed | Austral University of Chile, University of Chile and Institute Neurocirugia Dr Asenjo
Type: Journal Article | Journal: Oncotarget | Year: 2016
MRP1 transporter correlates positively with glioma malignancy and the Multiple Drug Resistance (MDR) phenotype in Glioblastoma Multiforme (GBM). Evidence shows that the MRP1 transporter is controlled by the adenosine signalling axis. The aim of this study was to identify the role of adenosine on the MDR phenotype in Glioblastoma Stem-like Cells (GSCs), the cell population responsible for the tumorigenic and chemoresistance capabilities of this tumour. We found that GSCs have increased intrinsic capacity to generate extracellular adenosine, thus controlling MRP1 transporter expression and activity via activation of the adenosine A3 receptor (A3AR). We showed PI3K/Akt and MEK/ERK1/2 signaling pathways downstream A3AR to control MRP1 in GSCs. In vitro pharmacological blockade of A3AR had a chemosensitizing effect, enhancing the actions of antitumour drugs and decreasing cell viability and proliferation of GSCs. In addition, we produced an in vivo xenograft model by subcutaneous inoculation of human GSCs in NOD/SCID-IL2Rg null mice. Pharmacological blockade of A3AR generated a chemosensitizing effect, enhancing the effectiveness of the MRP1 transporter substrate, vincristine, reducing tumour size and the levels of CD44 and Nestin stem cell markers as well as the Ki-67 proliferation indicator. In conclusion, we demonstrated the chemosensitizing effect of A3AR blockade on GSCs.
Rojas-Zalazar D.,Institute Neurocirugia Dr Asenjo |
Rojas-Zalazar D.,University of Chile |
Jorge Mura C.,Institute Neurocirugia Dr Asenjo |
Jorge Mura C.,University of Chile |
And 3 more authors.
Revista Chilena de Neuro-Psiquiatria | Year: 2011
Acromegaly is a chronic disease caused in most cases by hypophysiary adenoma. It is of complex management due to the high variability of the causing lesion and its clinical repercussion. Surgical outcomes are poor with remission rates of 80% for microadenomas and 50% for macroadenomas. The author's experience in treating 38 patients with this pathology as well as the remission results of the illness and the complications are presented herein. Handling alternatives and associated complications are discussed and a clinical case is presented to show the therapeutical options in more complex cases. © 2011 Sociedad de Neurología,siquiatría y Neurocirugía.
Cuevas J.L.,Institute Neurocirugia Dr Asenjo |
Cuevas J.L.,University of Chile |
Fernandez V.,Institute Neurocirugia Dr Asenjo |
Fernandez V.,University of Chile |
And 6 more authors.
Revista Medica de Chile | Year: 2013
Background: Dopamine agonists (DA) effectively reduce tumor size of macroprolactinomas, with the consequent improvement of eventual visual impairment. Aim: To study the visual outcomes in patients with macroprolactinoma treated with DA. Material and Methods: Retrospective cohort study which included patients with macroprolactinoma controlled at a Neuroendocrinology and Neuroophthalmology Department between 1997 and 2011, and treated exclusively with DA (bromocriptine or cabergoline). Patients who were operated or had previous radiotherapy and those with an incomplete follow up, were excluded. We analyzed and compared the visual status before and after the beginning of DA treatment. Results: Thirty one patients aged 8 to 59 years, were included. Eighteen patients (58%) had visual impairment at the moment of diagnosis (group 1) and 13 had no alterations (group 2). Mean follow up was 36.5 months. Fifteen patients from group 1 (83%) had visual improvement, two remained stable (11%) and one had a visual deterioration (6%). In group 2, only one non-compliant patient had a visual deterioration. Conclusions: DAs are effective in the management of neuro-ophthalmic complications associated to macroprolactinomas and should be considered as first choice therapy in these tumors.
Changes in cerebral blood flow velocity in supine and sitting position in patients with aneurysmal subarachnoid hemorrhage [Descripción de los cambios en la velocidad media de flujo sanguíneo cerebral en posición supino y sedente, en pacientes con hemorragia subaracnoidea aneurismática con vasoespasmo asintomático o sin vasoespasmo. Serie de casos]
Merino Osorio C.,University for Development |
Merino Osorio C.,Institute Neurocirugia Dr Asenjo |
Merino Osorio C.,University of Chile |
Heap P.,University of Chile |
And 4 more authors.
Revista Medica de Chile | Year: 2014
Background: Early mobilization in intensive care units (ICU) provides respiratory, neurological and cardiovascular benefits in hospitalized patients. However, the orthostatic effects of changing from a supine to a sitting position may interfere with cerebral hemodynamics of patients with aneurysmal subarachnoid hemorrhage (aSAH). Aim: To describe the changes in mean cerebral blood flow velocity (MCBFV) in supine and sitting position, in adult patients with aSAH, with asymptomatic vasospasm (AVS) or without vasospasm (VS) at a neurosurgical ICU. Material and Methods: Descriptive case series study in 21 patients with aSAH, both with and without VS. They were positioned in a supine 30° position and then seated at the edge of bed for six minutes. MCBFV was measured by transcranial Doppler (TCD), and hemodynamic variables in both positions were registered. After this basal assessment and for 21 days after the episode of SAH, patients were seated once a day and signs of VS were recorded. Results: No significant changes in MCBFV or hemodynamic variables were detected during position changes, except for an increase in heart rate in the sitting position. No patient with AVS at the onset, had symptomatic VS during the 21 days of follow up when patients were seated. Among patients with a normal MCBFV at baseline, five patients (24%) had VS at a mean of three days after the first time that they were seated on the edge of bed. Conclusions: Sitting patients at the edge of the bed is a safe mobilization alternative for patients who suffered aSAH who did not have VS or had AVS. © 2014, Sociedad Medica de Santiago. All rights reserved.
Riveros R.,El Salvador Hospital |
Riveros R.,Major University |
Chabriat H.,Hopital Lariboisiere |
Flores R.,Institute Neurocirugia Dr Asenjo |
And 3 more authors.
Frontiers in Neurology | Year: 2011
Objective: To examine the effect of donepezil for the treatment of cognitive and behavioral disorders associated with thalamic lesions in a 45-year-old male who suffered an infarct in the left thalamus. Background: Recent studies suggest that donepezil may improve executive functions impairments due to subcortical ischemic lesions. Method: The effects of donepezil were analyzed in a single-case of thalamic infarction with cognitive and behavioral alterations in an open label study. Results: Significant behavioral modifications related to improved performances in executive functions were observed with the treatment. Conclusion: The results suggest that donepezil may have significant effect on executive functions that can alter behavioral outcomes after thalamic infarctions. © 2011 Riveros, Chabriat, Flores, Alvarez and Slachevsky.
PubMed | Institute Neurocirugia Dr Asenjo
Type: Journal Article | Journal: Revista medica de Chile | Year: 2013
Dopamine agonists (DA) effectively reduce tumor size of macroprolactinomas, with the consequent improvement of eventual visual impairment.To study the visual outcomes in patients with macroprolactinoma treated with DA.Retrospective cohort study which included patients with macroprolactinoma controlled at a Neuro-endocrinology and Neuro-ophthalmology Department between 1997 and 2011, and treated exclusively with DA (bromocriptine or cabergoline). Patients who were operated or had previous radiotherapy and those with an incomplete follow up, were excluded. We analyzed and compared the visual status before and after the beginning of DA treatment.Thirty one patients aged 8 to 59 years, were included. Eighteen patients (58%) had visual impairment at the moment of diagnosis (group 1) and 13 had no alterations (group 2). Mean follow up was 36.5 months. Fifteen patients from group 1 (83%) had visual improvement, two remained stable (11 %) and one had a visual deterioration (6%). In group 2, only one non-compliant patient had a visual deterioration.DAs are effective in the management of neuro-ophthalmic complications associated to macroprolactinomas and should be considered as first choice therapy in these tumors.