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Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53

Tom Van Maerken UGent, Liesbeth Ferdinande UGent, Jasmien Taildeman UGent, Irina Lambertz UGent, Nurten Yigit UGent, Liesbeth Vercruysse UGent, Ali Rihani UGent, Martin Michaelis, Jindrich Cinatl and Claude Cuvelier UGent, et al. (2009) JOURNAL OF THE NATIONAL CANCER INSTITUTE. 101(22). p.1562-1574
abstract
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. 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)DOX(20)) or with mutant p53 (UKF-NB-3(r)VCR(10)). 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. Nutlin-3 induced a similar activation of the p53 pathway in UKF-NB-3 and UKF-NB-3(r)DOX(20) cells, as evidenced by increased expression of p53 target genes, G(1) cell cycle arrest, and induction of apoptosis. No such response was observed in UKF-NB-3(r)VCR(10) cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-3(r)DOX(20) 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 mm(3), difference = 890 mm(3), 95% confidence interval = 469 to 1311 mm(3), P < .001), p53 pathway activation, and reduction in the extent of metastatic disease. The growth of UKF-NB-3(r)VCR(10) xenografts was unaffected by nutlin-3. Nutlin-3 activates the p53 pathway and suppresses tumor growth in this model system of chemoresistant neuroblastoma, provided that wild-type p53 is present.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
keyword
CELL-DEATH, DOUBLE MINUTE-2, CONCOMITANT INHIBITION, ACUTE MYELOGENOUS LEUKEMIA, MULTIDRUG-RESISTANCE, TIME PCR PRIMER, P53-MEDIATED MITOCHONDRIAL APOPTOSIS, GENE-EXPRESSION, CHEMOTHERAPY-INDUCED APOPTOSIS, PROBE DATABASE
journal title
JOURNAL OF THE NATIONAL CANCER INSTITUTE
J. Natl. Cancer Inst.
volume
101
issue
22
pages
13 pages
publisher
OXFORD UNIV PRESS INC
place of publication
CARY
Web of Science type
Article
Web of Science id
000272086400010
JCR category
ONCOLOGY
JCR impact factor
14.069 (2009)
JCR rank
6/163 (2009)
JCR quartile
1 (2009)
ISSN
0027-8874
DOI
10.1093/jnci/djp355
language
English
UGent publication?
yes
classification
A1
id
837220
handle
http://hdl.handle.net/1854/LU-837220
date created
2010-01-25 15:16:13
date last changed
2012-06-26 14:31:55
@article{837220,
  abstract     = {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.

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)DOX(20)) or with mutant p53 (UKF-NB-3(r)VCR(10)). 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.

Nutlin-3 induced a similar activation of the p53 pathway in UKF-NB-3 and UKF-NB-3(r)DOX(20) cells, as evidenced by increased expression of p53 target genes, G(1) cell cycle arrest, and induction of apoptosis. No such response was observed in UKF-NB-3(r)VCR(10) cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-3(r)DOX(20) 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 mm(3), difference = 890 mm(3), 95\% confidence interval = 469 to 1311 mm(3), P {\textlangle} .001), p53 pathway activation, and reduction in the extent of metastatic disease. The growth of UKF-NB-3(r)VCR(10) xenografts was unaffected by nutlin-3.

Nutlin-3 activates the p53 pathway and suppresses tumor growth in this model system of chemoresistant neuroblastoma, provided that wild-type p53 is present.},
  author       = {Van Maerken, Tom and Ferdinande, Liesbeth and Taildeman, Jasmien and Lambertz, Irina and Yigit, Nurten and Vercruysse, Liesbeth and Rihani, Ali and Michaelis, Martin and Cinatl, Jindrich and Cuvelier, Claude and Marine, Jean-Christophe and De Paepe, Anne and Bracke, Marc and Speleman, Franki and Vandesompele, Jo},
  issn         = {0027-8874},
  journal      = {JOURNAL OF THE NATIONAL CANCER INSTITUTE},
  keyword      = {CELL-DEATH,DOUBLE MINUTE-2,CONCOMITANT INHIBITION,ACUTE MYELOGENOUS LEUKEMIA,MULTIDRUG-RESISTANCE,TIME PCR PRIMER,P53-MEDIATED MITOCHONDRIAL APOPTOSIS,GENE-EXPRESSION,CHEMOTHERAPY-INDUCED APOPTOSIS,PROBE DATABASE},
  language     = {eng},
  number       = {22},
  pages        = {1562--1574},
  publisher    = {OXFORD UNIV PRESS INC},
  title        = {Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53},
  url          = {http://dx.doi.org/10.1093/jnci/djp355},
  volume       = {101},
  year         = {2009},
}

Chicago
Van Maerken, Tom, Liesbeth Ferdinande, Jasmien Taildeman, Irina Lambertz, Nurten Yigit, Liesbeth Vercruysse, Ali Rihani, et al. 2009. “Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type P53.” Journal of the National Cancer Institute 101 (22): 1562–1574.
APA
Van Maerken, T., Ferdinande, L., Taildeman, J., Lambertz, I., Yigit, N., Vercruysse, L., Rihani, A., et al. (2009). Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 101(22), 1562–1574.
Vancouver
1.
Van Maerken T, Ferdinande L, Taildeman J, Lambertz I, Yigit N, Vercruysse L, et al. Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53. JOURNAL OF THE NATIONAL CANCER INSTITUTE. CARY: OXFORD UNIV PRESS INC; 2009;101(22):1562–74.
MLA
Van Maerken, Tom, Liesbeth Ferdinande, Jasmien Taildeman, et al. “Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type P53.” JOURNAL OF THE NATIONAL CANCER INSTITUTE 101.22 (2009): 1562–1574. Print.