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Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma

Lookup NU author(s): Dr Lindi Chen, Dr Yan ZhaoORCiD, Dr Gail Halliday, Philip Berry, Emeritus Professor Herbie Newell, Emeritus Professor John LunecORCiD, Professor Deborah TweddleORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).

Abstract

Background: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.Methods: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.Results: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.Conclusions: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.British Journal of Cancer advance online publication, 12 June 2014; doi:10.1038/bjc.2014.325 www.bjcancer.com.

Publication metadata

Author(s): Chen L, Zhao Y, Halliday GC, Berry P, Rousseau RF, Middleton SA, Nichols GL, Del Bello F, Piergentili A, Newell DR, Lunec J, Tweddle DA

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2014

Volume: 111

Pages: 716-725

Print publication date: 12/08/2014

Online publication date: 12/06/2014

Acceptance date: 13/05/2014

Date deposited: 08/01/2021

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/bjc.2014.325

DOI: 10.1038/bjc.2014.325

PubMed id: 24921920

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