Modulation of P-glycoprotein but not MRPI- or BCRP-mediated drug resistance by LY335979
Modulation of P-glycoprotein but not MRPI- or BCRP-mediated drug resistance by LY335979
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DOI：
10.1002/ijc.10792
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发表时间：
2003-01-01
影响因子：
6.4
通讯作者：
Dantzig, AH
中科院分区：
文献类型：
--
作者：
Shepard, RL;Cao, J;Dantzig, AH
我们的研究检查了LY 335979（Zosuquidar trihydrochloride）调节3种不同的ABC转运蛋白的能力，这些转运蛋白是耐药机制：P-糖蛋白（Pgp，ABCB 1），多药耐药相关蛋白（MRP 1，ABCC 2）和乳腺癌耐药蛋白（BCRP，ABCG 2）。Pgp介导的抗性可以通过与高效选择性抑制剂LY 335979共同施用来调节。使用一组HL 60白血病细胞系或MCF-7乳腺癌转染子，在3天细胞毒性试验中检查了米托蒽醌和长春瑞滨（2种用于治疗某些实体瘤的药物）对耐药性的调节。0.5 μ M的LY 335979基本上逆转了Pgp的米托蒽醌耐药性并完全逆转了长春瑞滨耐药性。表达HL 60/Vinc细胞。然而，LY 335979没有调节MRP 1表达的HL 60/ADR或药物敏感的亲代HL 60细胞的耐药性。为了确定LY 335979是否调节BCRP介导的耐药性，评价了26倍米托蒽醌耐药性、BCRP转染的MCF-7细胞的敏感性。加入5 μ M的LY 335979，浓度比Pgp的亲和力高100倍，对BCRP转染子几乎没有影响。[I-125]碘多霉素光标记CEM/VLB 100膜中的Pgp，并被5 μ M LY 335979和GF 120918抑制。在H69 AR或MCF-7/BCRP膜中分别未发生MRP或BCRP的光标记。这些结果进一步表明，LY 335979对Pgp具有高度特异性，并且不调节MRP 1或BCRP介导的耐药性，并且可与米托蒽醌和长春瑞滨联合用于肿瘤细胞。(C)2002 Wiley-Liss，Inc.
Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P-glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp-mediated resistance can be modulated by co-administration with the highly potent, selective inhibitor LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3-day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF-7 breast cancer transfectants. LY335979, at 0.5 muM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp. expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1-expressing HL60/ADR or drug-sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP-mediated drug resistance, the sensitivity of 26-fold mitoxantrone resistant, BCRP-transfected MCF-7 cells was evaluated. Addition of 5 muM LY335979, a concentration similar to100-fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [I-125]Iodomycin photolabeled Pgp in CEM/VLB100 membranes and was inhibited by 5 muM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF-7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1- or BCRP-mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells. (C) 2002 Wiley-Liss, Inc.