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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Multidrug resistance (MDR) in cancers often involves ATP-binding cassette transporters like Multi-Drug Resistance Protein 1 (MDR-1).
• Nutlin-3, an MDM2-p53 antagonist, has shown potential as an MDR-1 inhibitor.

Purpose of the Study:

• To investigate if other MDM2-p53 antagonists (MI-63, NDD0005, RG7388) can modulate MDR-1 function.
• To assess this modulation in p53 mutant neuroblastoma cells.

Main Methods:

• Utilized XTT-based cell viability assays.
• Employed western blotting.
• Conducted liquid chromatography-mass spectrometry analysis.

Main Results:

• MDM2-p53 antagonists potentiated vincristine's growth inhibition in MDR-1-high neuroblastoma cells.
• Verapamil, Nutlin-3, MI-63, and NDD0005 increased intracellular vincristine levels, unlike RG7388.
• These effects were observed at non-cytotoxic concentrations for the antagonists alone.

Conclusions:

• Structurally diverse MDM2-p53 antagonists can inhibit MDR-1.
• These compounds can reverse MDR-1-mediated drug resistance in neuroblastoma cells, irrespective of p53 status.
• Findings are crucial for designing clinical trials involving MDM2-p53 antagonists and MDR-1 substrates.