Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein.
Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein.
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DOI：
10.1016/j.bcp.2004.05.052
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发表时间：
2004-10
影响因子：
5.8
通讯作者：
Xin Wang;T. Nitanda;Minyi Shi;M. Okamoto;T. Furukawa;Y. Sugimoto;S. Akiyama;M. Baba
中科院分区：
文献类型：
--
作者：
Xin Wang;T. Nitanda;Minyi Shi;M. Okamoto;T. Furukawa;Y. Sugimoto;S. Akiyama;M. Baba
乳腺癌耐药蛋白(BCRP/ABCG2)是一种新的三磷酸腺苷结合盒转运蛋白，可诱导肿瘤细胞产生多药耐药。我们以前曾报道过，人类免疫缺陷病毒1型(HIV-1)的核苷类逆转录酶抑制剂(NRTI)在CD4+T细胞中的高水平表达导致了细胞对NRTI的抵抗。然而，该BCRP被发现在第482位(BCRPR482M)有Arg到Met的突变。目前的研究表明，野生型BCRP(BCRPWT)也使细胞对NRTIs产生抵抗。建立了高表达BCRPWT(MT-4/BCRP)的MT-4细胞系，并通过基因分型和表型分析证实了BCRPWTT的表达。与亲代MT-4细胞相比，MT-4/BCRP细胞对齐多夫定(AZT)表现出抗病毒活性和药物细胞毒性。此外，其他NRTI对MT-4/BCRP细胞中HIV-1复制的抑制作用也弱于MT-4细胞。MT-4/BCRP细胞内AZT积聚明显减少。对AZT细胞内代谢的分析表明，耐药是由于MT-4/BCRP细胞中AZT及其代谢物外流增加所致。此外，BCRP特异性抑制剂Fumitremorgin C完全恢复MT-4/BCRP细胞AZT的减少。这些结果表明，与BCRPR482M一样，BCRPWT1在细胞对NRTIs的抗性中也发挥着重要作用。
Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We previously reported that a high level of BCRP expression in CD4+T cells conferred cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs) of human immunodeficiency virus type 1 (HIV-1). However, this BCRP was found to have a mutation of Arg to Met at position 482 (BCRPR482M). The present study demonstrated that the wild-type BCRP (BCRPWT) also conferred cellular resistance to NRTIs. MT-4 cells (a CD4+T-cell line) highly expressing BCRPWT(MT-4/BCRP) were generated and the expression of BCRPWTwas confirmed by genotypic and phenotypic analyses. Compared to the parental MT-4 cells, MT-4/BCRP cells displayed resistance to zidovudine (AZT) in terms of antiviral activity as well as drug cytotoxicity. In addition, other NRTIs were also less inhibitory to HIV-1 replication in MT-4/BCRP cells than in MT-4 cells. Significant reduction of intracellular AZT accumulation was observed in MT-4/BCRP cells. An analysis for intracellular metabolism of AZT suggested that the resistance was attributed to the increased efflux of AZT and its metabolites in MT-4/BCRP cells. Furthermore, the BCRP-specific inhibitor fumitremorgin C completely restored the reduction of AZT in MT-4/BCRP cells. These results indicate that, like BCRPR482M, BCRPWTalso plays an important role in cellular resistance to NRTIs.