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

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.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

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

doi

10.1038/bjc.2014.325

subject

Has Abstract

pub_date

2014-08-12 00:00:00

pages

716-25

issue

4

eissn

0007-0920

issn

1532-1827

pii

bjc2014325

journal_volume

111

pub_type

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