Reversal of P-glycoprotein-Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3
Reversal of P-glycoprotein-Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3
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DOI：
10.1158/0008-5472.can-08-1856
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Cinatl, Jindrich, Jr.
中科院分区：
文献类型：
--
作者：
Michaelis, Martin;Rothweiler, Florian;Cinatl, Jindrich, Jr.
小鼠双分钟2 （MDM2）负向调节肿瘤抑制蛋白p53的活性。Nutlin-3是一种MDM2抑制剂，作为p53通路的非基因毒性激活剂用于癌症治疗，目前正在临床前研究中。本研究评估了nutin -3在化疗敏感和耐药的神经母细胞瘤和横纹肌肉瘤细胞系中单独或联合化疗药物的抗肿瘤作用。在p53野生型细胞株（IC（50）和17 μ mol/L）中，nutin -3单一处理的效果更为明显。与预期形成鲜明对比的是，不影响p53突变细胞系活力的坚果素-3浓度，在p53突变、p -糖蛋白（P-gp）过表达的细胞系中，显著提高了vincristine的疗效（IC（50）降低了92- 3434倍）。其他P-gp底物也得到了类似的结果。此外，nutlin-3还能减少罗丹明123和其他荧光染料在P-gp中外排。对Madin-Darby犬肾（MDCK） II细胞稳定转染编码P-gp （MDCKII MDR1）或多药耐药蛋白I （MRP-1, MDCKII MRP1）的质粒的研究表明，nutlin-3不仅干扰P-gp，还影响MRP-1介导的外排。动力学研究和对P-gp- atp酶活性的研究表明，nutlin-3可能作为P-gp转运底物。对nutlin-3对映体nutlin-3a和nutlin-3b的检测显示，与仅限于nutlin-3a的mdm2抑制活性相反，这两种对映体类似地干扰p- gp介导的药物外排。综上所述，本报道发现了nutlin-3对P-gp和MRP-1的抑制作用是该物质的一种新的抗癌机制。[癌症研究2009；69 (2): 416 - 21)
Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC(50)s 17 mu mol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC(50)s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein I (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416-21]