Journal of the National Cancer Institute Advance Access published online on November 10, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp355
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© The Author 2009. Published by Oxford University Press.
ARTICLE |
Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53
Affiliations of authors: Center for Medical Genetics (TVM, NY, LV, AR, ADP, FS, JV), Department of Clinical Chemistry, Microbiology and Immunology (TVM), Department of Pathology (LF, JT, CAC), and Laboratory of Experimental Cancerology (MB), Ghent University Hospital, Ghent, Belgium; Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology–Ghent University (VIB-UGent), Ghent, Belgium (IL, J-CM); Zentrum der Hygiene, Institut für Medizinische Virologie, Klinikum der J.W. Goethe Universität, Frankfurt am Main, Germany (MM, JC)
Correspondence to: Tom Van Maerken, MD, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium (e-mail: tom.vanmaerken{at}ugent.be).
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-3rDOX20) or with mutant p53 (UKF-NB-3rVCR10). 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-3rDOX20 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-3rVCR10 cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-3rDOX20 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-3rVCR10 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.
| CONTEXT AND CAVEATS Prior knowledge Survival rates of patients with high-risk neuroblastoma remain low because of resistance to conventional chemotherapeutic agents. p53 is a powerful tumor suppressor protein. Mutations in p53 that lead to its inactivation are rare in neuroblastoma. MDM2, a natural inhibitor of p53 that may have an increased activity in neuroblastoma, is a potential therapeutic target. Study design In vitro and in vivo analysis of the effects of the small-molecule MDM2 antagonist nutlin-3 on p53 activity and tumor growth in an established model system of multidrug-resistant neuroblastoma. Contribution Nutlin-3 activated the p53 pathway, irrespective of sensitivity to chemotherapeutic drugs, in neuroblastoma cells with wild-type p53 but not in cells with mutant p53. Oral administration of nutlin-3 as a single agent reduced tumor growth and metastasis in the presence of wild-type p53. Implications Nutlin-3 may be a viable treatment option for advanced-stage and chemoresistant neuroblastoma with wild-type p53. Limitations It is possible that the findings in this model system cannot be generalized to all cases of chemoresistant neuroblastoma with wild-type p53. From the Editors
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Manuscript received March 2, 2009; revised August 21, 2009; accepted September 11, 2009.
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J Natl Cancer Inst 2009 101: 1523.
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