title: Combined use of anticancer drugs and an inhibitor of multiple drug resistance-associated protein-1 increases sensitivity and decreases survival of glioblastoma multiforme cells in vitro.
abstract: 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.
authors.affiliation: Instituto de Bioquímica, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, P.O. box 567, Valdivia, Chile.
authors.forename: Lilia
authors.initials: L
authors.lastname: Peigñan
authors.forename: Wallys
authors.initials: W
authors.lastname: Garrido
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Segura
authors.forename: Rómulo
authors.initials: R
authors.lastname: Melo
authors.forename: David
authors.initials: D
authors.lastname: Rojas
authors.forename: Juan Guillermo
authors.initials: JG
authors.lastname: Cárcamo
authors.forename: Rody
authors.initials: R
authors.lastname: San Martín
authors.forename: Claudia
authors.initials: C
authors.lastname: Quezada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002648:Child; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014750:Vincristine; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1