ABSTRACT
BACKGROUND: Mortality rate is dramatically high in high grade brain tumors. The presence of multiple drug resistance transporters in glioblastoma multiforme, has contributed largely to the poor efficacy of targeted therapy against cancer in the central nervous system. AIM: To analyze the percentage of survival and mortality of patients with glioblastoma multiforme in a cohort of patients in Chile and to co-rrelate the chemo-resistance of these cells with the expression level of multiple drug resistance transporters. MATERIALS AND METHODS: Eighteen biopsies of glioblastoma multiforme were obtained from patients at the Institute of Neurosurgery Dr. Asenjo (INCA). The tumor cells were obtained from primary cultures and the expression and activity of multiple drug resistance transporters was assessed by RT-PCR and immunohistochemistry. Population-based study was performed using the databases of the Department of Neurosurgery of INCA. RESULTS: The number of patients with glioblastoma multiforme increased between 2007 and 2009, from 3.5% to 7.9% of total brain tumors. Mortality of these tumors is 90 % at three years. A high expression and activity of the multiple drugs resistance associated protein 1 (Mrp1) transporter was observed in primary cultures of biopsies. CONCLUSIONS: We propose that Mrp1 activity is responsible for the chemo-resistance of the glioblastoma multiforme and inhibition of this transporter could represent a plausible strategy for the treatment.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Brain Neoplasms/drug therapy , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Neoplasm Proteins/metabolism , Adolescent , Adult , Aged , Brain Neoplasms/metabolism , Brain Neoplasms/mortality , Child , Child, Preschool , Cohort Studies , Female , Follow-Up Studies , Glioblastoma/metabolism , Glioblastoma/mortality , Humans , Immunohistochemistry , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Tumor Cells, Cultured , Young AdultABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Brain Neoplasms/drug therapy , Cell Line, Tumor/drug effects , Cell Survival/drug effects , Glioblastoma/drug therapy , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Brain Neoplasms/pathology , Child , Drug Therapy, Combination , Etoposide/pharmacology , Etoposide/therapeutic use , Glioblastoma/pathology , Humans , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Vincristine/pharmacology , Vincristine/therapeutic useABSTRACT
Background: Mortality rate is dramatically high in high grade brain tumors. The presence of multiple drug resistance transporters in glioblastoma multiforme, has contributed largely to the poor effcacy of targeted therapy against cancer in the central nervous system. Aim: To analyze the percentage of survival and mortality of patients with glioblastoma multiforme in a cohort of patients in Chile and to co-rrelate the chemo-resistance of these cells with the expression level of multiple drug resistance transporters. Materials and Methods: Eighteen biopsies of glioblastoma multiforme were obtained from patients at the Institute of Neurosurgery Dr. Asenjo (INCA). The tumor cells were obtained from primary cultures and the expression and activity of multiple drug resistance transporters was assessed by RT-PCR and immunohistochemistry. Population-based study was performed using the databases of the Department of Neurosurgery of INCA. Results: The number of patients with glioblastoma multiforme increased between 2007 and 2009, from 3.5 percent to 7.9 percent of total brain tumors. Mortality of these tumors is 90 percent at three years. A high expression and activity of the multiple drugs resistance associated protein 1 (Mrp1) transporter was observed in primary cultures of biopsies. Conclusions: We propose that Mrp1 activity is responsible for the chemo-resistance of the glioblastoma multiforme and inhibition of this transporter could represent a plausible strategy for the treatment.
