Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma.
Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma.
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DOI：
10.1038/bjc.2014.325
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发表时间：
2014-08-12
影响因子：
8.8
通讯作者：
Tweddle, D. A.
中科院分区：
文献类型：
--
作者：
Chen, L.;Zhao, Y.;Halliday, G. C.;Berry, P.;Rousseau, R. F.;Middleton, S. A.;Nichols, G. L.;Del Bello, F.;Piergentili, A.;Newell, D. R.;Lunec, J.;Tweddle, D. A.
人类癌症中获得性多药耐药的常见机制是ATP结合盒转运蛋白如多药耐药蛋白1（MDR-1）的过表达。Nutlin-3是一种MDM 2-p53拮抗剂，以前曾报道是一种竞争性MDR-1抑制剂。本研究使用基于XTT的细胞活力测定、蛋白质印迹和液相色谱-质谱分析，评估了结构不同的MDM 2-p53拮抗剂MI-63、NDD 0005和RG 7388是否也能够调节MDR-1功能，特别是在p53突变型神经母细胞瘤细胞中。当维拉帕米和MDM 2-p53拮抗剂与高MDR-1表达p53突变型神经母细胞瘤细胞系联合使用时，以浓度依赖性方式增强长春新碱介导的生长抑制作用，单独给药时浓度不影响细胞活力。液相色谱-质谱分析显示，维拉帕米、Nutlin-3、MI-63和NDD 0005（而非RG 7388）导致MDR-1高表达细胞系中长春新碱的细胞内水平升高。这些结果表明，除了Nutlin-3，其他结构无关的MDM 2-p53拮抗剂也可以作为MDR-1抑制剂，逆转MDR-1介导的多药耐药的神经母细胞瘤细胞系中的p53非依赖性的方式。这些发现对于MDM 2-p53拮抗剂与MDR-1底物药物联合使用时的未来临床试验设计非常重要。
A frequent mechanism of acquired multidrug resistance in human cancers is overexpression of ATP-binding cassette transporters such as the Multi-Drug Resistance Protein 1 (MDR-1). Nutlin-3, an MDM2–p53 antagonist, has previously been reported to be a competitive MDR-1 inhibitor. This study assessed whether the structurally diverse MDM2–p53 antagonists, MI-63, NDD0005, and RG7388 are also able to modulate MDR-1 function, particularly in p53 mutant neuroblastoma cells, using XTT-based cell viability assays, western blotting, and liquid chromatography–mass spectrometry analysis. Verapamil and the MDM2–p53 antagonists potentiated vincristine-mediated growth inhibition in a concentration-dependent manner when used in combination with high MDR-1-expressing p53 mutant neuroblastoma cell lines at concentrations that did not affect the viability of cells when given alone. Liquid chromatography–mass spectrometry analyses showed that verapamil, Nutlin-3, MI-63 and NDD0005, but not RG7388, led to increased intracellular levels of vincristine in high MDR-1-expressing cell lines. These results show that in addition to Nutlin-3, other structurally unrelated MDM2–p53 antagonists can also act as MDR-1 inhibitors and reverse MDR-1-mediated multidrug resistance in neuroblastoma cell lines in a p53-independent manner. These findings are important for future clinical trial design with MDM2–p53 antagonists when used in combination with agents that are MDR-1 substrates.
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影响因子：
11.2
作者：
Michaelis, Martin;Rothweiler, Florian;Cinatl, Jindrich, Jr.
通讯作者：
Cinatl, Jindrich, Jr.
影响因子：
3.5
作者：
Miyazaki, Masaki;Naito, Hiroyuki;Soga, Tsunehiko
通讯作者：
Soga, Tsunehiko
DOI：
10.1073/pnas.94.20.11037
发表时间：
1997-09-30
影响因子：
11.1
作者：
Thottassery, JV;Zambetti, GP;Schuetz, JD
通讯作者：
Schuetz, JD
影响因子：
8.4
作者：
Haber, M;Bordow, SB;Norris, MD
通讯作者：
Norris, MD
影响因子：
158.5
作者：
CHAN, HSL;HADDAD, G;LING, V
通讯作者：
LING, V