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

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

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

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.

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15751 United Kingdom CRUK_ Cancer Research UK

0 (ABCB1 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily B)
0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
0 (Antineoplastic Agents)
0 (Imidazoles)
0 (Indoles)
0 (MI-63 compound)
0 (Piperazines)
0 (Pyrrolidines)
0 (RG7388)
0 (Spiro Compounds)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
0 (para-Aminobenzoates)
53IA0V845C (nutlin 3)
5J49Q6B70F (Vincristine)
80168379AG (Doxorubicin)
CJ0O37KU29 (Verapamil)
EC 2.3.2.27 (MDM2 protein, human)
EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
Q20Q21Q62J (Cisplatin)

Date Created: 20140613 Date Completed: 20141006 Latest Revision: 20240210

20250114

PMC4134492

10.1038/bjc.2014.325

24921920