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

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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.
Keywords
DOUBLE MINUTE-2, CELL-DEATH, CONCOMITANT INHIBITION, ACUTE MYELOGENOUS LEUKEMIA, MULTIDRUG-RESISTANCE, TIME PCR PRIMER, P53-MEDIATED MITOCHONDRIAL APOPTOSIS, GENE-EXPRESSION, CHEMOTHERAPY-INDUCED APOPTOSIS, PROBE DATABASE

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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.
@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      = {DOUBLE MINUTE-2,CELL-DEATH,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},
}

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