title: 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.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Halliday
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: P
authors.initials: P
authors.lastname: Berry
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Rousseau
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Middleton
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Nichols
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, via S. Agostino 1, Camerino 62032, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, via S. Agostino 1, Camerino 62032, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lunec
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Tweddle
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; C543589:MI-63 compound; D010879:Piperazines; D011759:Pyrrolidines; C586849:RG7388; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; C482205:nutlin 3; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin