Title: Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53
Authors: Van Maerken, Tom ×
Ferdinande, Liesbeth
Taildeman, Jasmien
Lambertz, Irina
Yigit, Nurten
Vercruysse, Liesbeth
Rihani, Ali
Michaelis, Martin
Cinatl, Jindrich
Cuvelier, Claude A
Marine, Chris
De Paepe, Anne
Bracke, Marc
Speleman, Frank
Vandesompele, Jo #
Issue Date: Nov-2009
Publisher: Oxford University Press
Series Title: Journal of the National Cancer Institute vol:101 issue:22 pages:1562-74
Abstract: BACKGROUND: Restoring p53 function by antagonizing its interaction with the negative regulator MDM2 is an appealing nongenotoxic approach to treating tumors with wild-type p53. Mutational inactivation of p53 is rare in neuroblastoma tumors at diagnosis and occurs in only a subset of multidrug-resistant neuroblastomas. METHODS: The antiproliferative and cytotoxic effect of nutlin-3, a small-molecule MDM2 antagonist, was examined in chemosensitive (UKF-NB-3) and matched chemoresistant neuroblastoma cells with wild-type p53 (UKF-NB-3(r)DOX20) or with mutant p53 (UKF-NB-3(r)VCR10). Activation of the p53 pathway was assessed by expression analysis of p53 target genes, flow cytometric cell cycle analysis, and apoptosis assays. Mice with established chemoresistant tumor xenografts were treated orally with nutlin-3 or vehicle control (n = 5-10 mice per group) and were used to evaluate effects on tumor growth, p53 pathway activity, and metastatic tumor burden. All statistical tests were two-sided. RESULTS: Nutlin-3 induced a similar activation of the p53 pathway in UKF-NB-3 and UKF-NB-3(r)DOX20 cells, as evidenced by increased expression of p53 target genes, G1 cell cycle arrest, and induction of apoptosis. No such response was observed in UKF-NB-3(r)VCR10 cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-3(r)DOX20 xenograft-bearing mice led to inhibition of primary tumor growth (mean tumor volume after 3 weeks of treatment, nutlin-3- vs vehicle-treated mice: 772 vs 1661 mm3, difference = 890 mm3, 95% confidence interval = 469 to 1311 mm3, P < .001), p53 pathway activation, and reduction in the extent of metastatic disease. The growth of UKF-NB-3(r)VCR10 xenografts was unaffected by nutlin-3. CONCLUSIONS: Nutlin-3 activates the p53 pathway and suppresses tumor growth in this model system of chemoresistant neuroblastoma, provided that wild-type p53 is present.
ISSN: 0027-8874
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Molecular Cancer Biology
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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