Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative.
Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative.
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DOI：
10.1038/bjc.1998.597
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发表时间：
1998-10
影响因子：
8.8
通讯作者：
Bevan P
中科院分区：
文献类型：
--
作者：
Dale IL;Tuffley W;Callaghan R;Holmes JA;Martin K;Luscombe M;Mistry P;Ryder H;Stewart AJ;Charlton P;Twentyman PR;Bevan P
XR9051Zinylidene((N-(4-(2-(6，7-Dimethoxy-1，2，3，4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z，6Z)-6-benzylidene-1-methyl-2，5-dioxo-3-pipera)甲基苯甲酰胺)被确定为P-糖蛋白介导的多药耐药的有效调节剂，此前基于一种天然产物先导化合物的合成化学程序被确定为有效的调节剂。用一组人和小鼠耐药细胞系(H69/LX4、2780AD、EMT6/AR 1.0、MC26和P388/DX Johnson)测定XR9051的活性。XR9051能够逆转包括阿霉素、依托泊苷和长春新碱在内的多种细胞毒药物的耐药性，这些药物与经典的MDR有关。在0.3-0.5微米的浓度下，XR9051能够使耐药细胞对细胞毒药物完全增敏，而对相应的亲本细胞株几乎没有影响。未观察到XR9051对非耐药细胞毒物甲氨蝶呤和5-氟尿嘧啶的反应。在所有使用的检测中，XR9051始终比环孢素A(CsA)和维拉帕米(VPM)更有效。与CsA和VPM不同的是，XR9051可抑制[~3H]柔红霉素从预加载细胞中外流，并且在去除抗性修饰剂后仍保持活性数小时。在[~3H]叠氮多宾的光亲和标记实验中，XR9051能够取代P-糖蛋白的结合。在[~3H]长春花碱的结合研究中，XR9051被证明是一种有效的细胞毒与P-糖蛋白结合的抑制剂(EC50=1.4+/-0.5 nM)。综上所述，这些结果表明XR9051通过与P-糖蛋白直接相互作用来逆转MDR表型。
XR9051 (N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene) methylbenzamide) was identified as a potent modulator of P-glycoprotein-mediated multidrug resistance (MDR) following a synthetic chemistry programme based on a natural product lead compound. The activity of XR9051 was determined using a panel of human and murine drug-resistant cell lines (H69/LX4, 2780AD, EMT6/AR 1.0, MC26 and P388/DX Johnson). XR9051 was able to reverse resistance to a variety of cytotoxic drugs, including doxorubicin, etoposide and vincristine, which are associated with classical MDR. At a concentration of 0.3-0.5 microM, XR9051 was able to fully sensitize resistant cells to cytotoxics, whereas little or no effect was observed on the corresponding parental cell lines. No effect of XR9051 was observed on the response of cells to non-MDR cytotoxics such as methotrexate and 5-fluorouracil. XR9051 was consistently more potent than cyclosporin A (CsA) and verapamil (Vpm) in all assays used. XR9051 inhibited the efflux of [3H]daunorubicin from preloaded cells and, unlike CsA and Vpm, remained active for several hours after removal of resistance-modifying agent. In photoaffinity labelling experiments employing [3H]azidopine, XR9051 was able to displace binding to P-glycoprotein. In binding studies using [3H]vinblastine, XR9051 was shown to be a potent inhibitor of the binding of the cytotoxic to P-glycoprotein (EC50 = 1.4 +/- 0.5 nM). Taken together, the results indicate that XR9051 reverses the MDR phenotype through direct interaction with P-glycoprotein.