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.

• Authors: L Chen, Y Zhao, G C Halliday, P Berry, R F Rousseau, S A Middleton, G L Nichols, F Del Bello, A Piergentili, D R Newell, J Lunec, D A Tweddle
• Journal: British journal of cancer (Br J Cancer) Vol. 111 Issue 4 Pg. 716-25 (Aug 12 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 24921920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Imidazoles
• Indoles
• MI-63 compound
• Piperazines
• Pyrrolidines
• RG7388
• Spiro Compounds
• TP53 protein, human
• Tumor Suppressor Protein p53
• para-Aminobenzoates
• nutlin 3
• Vincristine
• Doxorubicin
• Verapamil
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents (metabolism, pharmacology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Inhibitory Concentration 50
• Neuroblastoma (drug therapy, metabolism)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Pyrrolidines (pharmacology)
• Spiro Compounds (pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)
• Verapamil (pharmacology)
• Vincristine (metabolism, pharmacology)
• para-Aminobenzoates (pharmacology)