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 cassette superfamily (ABC) of transporters, which are involved in ATP-dependent transport of hydrophobic compounds. One of the MRP family, MRP1, is partially associated with the multidrug resistance phenotype in brain tumors. In this study, we asked whether another MRP family gene, MRP3, could affect drug sensitivity to anticancer agents in human glioma cell lines and clinical glioma specimens. We first produced two antisense transfectants by introduction of antisense MRP3 cDNA into the glioma cell line NHG2, which endogenously 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 changed. 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 cisplatin. We next compared the mRNA levels of four ABC transporters, multidrug resistance 1 (MDR1), MRP1, MRP2 and MRP3 in clinical samples, including 34 patients with gliomas, by quantitative RT-PCR analysis. In some of the clinical samples, increased expression of MRP1 and MRP3 was apparent in malignant gliomas. In situ hybridization revealed that glioma cells were stained with MRP3 probe. MRP3 may modulate drug sensitivity to certain anticancer agents in human gliomas.
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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S
Haga
E
E
Hinoshita
K
K
Ikezaki
M
M
Fukui
G L
GL
Scheffer
T
T
Uchiumi
M
M
Kuwano
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016373:DNA, Antisense / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D016373:DNA, Antisense; D004273:DNA, Neoplasm; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C095122:multidrug resistance protein 3