Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma

The multidrug resistance protein (MRP) family belongs to the ATP-binding ca ssette superfamily (ABC) of transporters, which are involved in ATP-depende nt transport of hydrophobic compounds. One of the MRP family, MRP1, is part ially associated with the multidrug resistance phenotype in brain tumors. I n this study, we asked whether another MRP family gene, MRP3, could affect drug sensitivity to anticancer agents in human glioma cell lines and clinic al glioma specimens. We first produced two antisense transfectants by intro duction of antisense MRP3 cDNA into the glioma cell line NHG2, which endoge nously expresses MRP3. The two MRP3 antisense transfectants showed 2- to 5- fold increases in drug sensitivity to etoposide and cisplatin compared with NHG2 cells, but their sensitivity to vincristine or nitrosourea was not ch anged. Two MRP3 cDNA sense transfectants of pig kidney cell lines showed 4- to 6-fold drug resistance to etoposide, but only 1.4- to 1.5-fold to cispl atin. We next compared the mRNA levels of four ABC transporters, multidrug resistance 1 (MDR1), MIRP2, MRP2 and MRP3 in clinical samples, including 34 patients with gliomas, by quantitative RT-PCR analysis. In some of the cli nical samples, increased expression of MRP1 and mRP3 was apparent in malign ant gliomas. In situ hybridization revealed that glioma cells were stained with MRP3 probe. MRP3 may modulate drug sensitivity to certain anticancer a gents in human gliomas.