Multidrug resistance-associated protein MRP1 expression in human gliomas: chemosensitization to vincristine and etoposide by indomethacin in human glioma cell lines overexpressing MRP1.
The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated. When evaluated in tumor samples, MRP1 expression was observed in all of them with more than 90% of stained tumor cells in 14/15 high-grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular endothelial cells in the same 14 tumor samples, suggesting that the permeability to anticancer drugs could be also limited across brain tumor vessels. At concentrations comprised between 5 and 50 microM, indomethacin significantly increased the cytotoxic effect of etoposide in both cell lines but it was more efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with 8MG cells. These results suggest that the association of indomethacin to VCR or etoposide could be of interest in the clinical management of gliomas.
Benyahia
B
B
Department of Neurology Mazarin (AP-HP) and INSERM U495, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. baya.benyahia@psl.ap-hop-paris.fr
Huguet
S
S
Declèves
X
X
Mokhtari
K
K
Crinière
E
E
Bernaudin
J F
JF
Scherrmann
J M
JM
Delattre
J Y
JY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D005047:Etoposide; D007213:Indomethacin