Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma
Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma
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DOI：
10.1111/j.1349-7006.2001.tb01084.x
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发表时间：
2001-02-01
期刊：
影响因子：
--
通讯作者：
Kuwano, M
中科院分区：
文献类型：
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作者：
Haga, S;Hinoshita, E;Kuwano, M
多药耐药蛋白（MRP）家族属于转运蛋白的ATP结合盒超家族（ABC），参与疏水性化合物的ATP依赖性转运。 MRP 家族之一 MRP1 与脑肿瘤的多药耐药表型部分相关。在这项研究中，我们询问另一个 MRP 家族基因 MRP3 是否会影响人类神经胶质瘤细胞系和临床神经胶质瘤标本中对抗癌药物的敏感性。我们首先通过将反义MRP3 cDNA引入内源表达MRP3的神经胶质瘤细胞系NHG2中来产生两种反义转染子。与NHG2细胞相比，两种MRP3反义转染子对依托泊苷和顺铂的药物敏感性增加了2至5倍，但它们对长春新碱或亚硝基脲的敏感性没有改变。猪肾细胞系的两个 MRP3 cDNA 有义转染子对依托泊苷显示出 4 至 6 倍的耐药性，但对顺铂的耐药性仅为 1.4 至 1.5 倍。接下来，我们通过定量 RT-PCR 分析比较了临床样本（包括 34 名神经胶质瘤患者）中四种 ABC 转运蛋白、多药耐药 1 (MDR1)、MIRP2、MRP2 和 MRP3 的 mRNA 水平。在一些临床样本中，恶性胶质瘤中 MRP1 和 mRP3 的表达明显增加。原位杂交显示神经胶质瘤细胞被 MRP3 探针染色。 MRP3 可以调节人类神经胶质瘤对某些抗癌药物的药物敏感性。
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), MIRP2, 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.