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Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma

Tom Van Maerken UGent, Franki Speleman UGent, J VERMEULEN, Irina Lambertz UGent, Sarah De Clercq UGent, Els De Smet UGent, Nurten Yigit UGent, V COPPENS, Jan Philippé UGent and Anne De Paepe UGent, et al. (2006) CANCER RESEARCH. 66(19). p.9646-9655
abstract
Circumvention of the p53 tumor suppressor barrier in neuroblastoma is rarely caused by TP53 mutation but might arise from inappropriately increased activity of its principal negative regulator MDM2. We show here that targeted disruption of the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3 stabilizes p53 and selectively activates the p53 pathway in neuroblastoma cells with wildtype p53, resulting in a pronounced antiproliferative and cytotoxic effect through induction of G(1) cell cycle arrest and apoptosis. A nutlin-3 response was observed regardless of MYCN amplification status. Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference. The diversity of cellular responses reveals piciotropic mechanisms of nutlins to disable neuroblastoma cells and exemplifies the feasibility of exploiting, by a single targeted intervention, the multiplicity of anticancer activities exerted by a key tumor suppressor as p53. The observed treatment effects without the need of imposing a genotoxic burden suggest that selective MDM2 antagonists might be beneficial for treatment of neuroblastoma patients with and without MYCN amplification.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
journal title
CANCER RESEARCH
Cancer Res.
volume
66
issue
19
pages
9646-9655 pages
Web of Science type
Article
Web of Science id
000241014200039
JCR category
ONCOLOGY
JCR impact factor
7.656 (2006)
JCR rank
10/125 (2006)
JCR quartile
1 (2006)
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-06-0792
language
English
UGent publication?
yes
classification
A1
id
364510
handle
http://hdl.handle.net/1854/LU-364510
date created
2007-02-28 16:20:00
date last changed
2012-06-26 14:31:05
@article{364510,
  abstract     = {Circumvention of the p53 tumor suppressor barrier in neuroblastoma is rarely caused by TP53 mutation but might arise from inappropriately increased activity of its principal negative regulator MDM2. We show here that targeted disruption of the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3 stabilizes p53 and selectively activates the p53 pathway in neuroblastoma cells with wildtype p53, resulting in a pronounced antiproliferative and cytotoxic effect through induction of G(1) cell cycle arrest and apoptosis. A nutlin-3 response was observed regardless of MYCN amplification status. Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference. The diversity of cellular responses reveals piciotropic mechanisms of nutlins to disable neuroblastoma cells and exemplifies the feasibility of exploiting, by a single targeted intervention, the multiplicity of anticancer activities exerted by a key tumor suppressor as p53. The observed treatment effects without the need of imposing a genotoxic burden suggest that selective MDM2 antagonists might be beneficial for treatment of neuroblastoma patients with and without MYCN amplification.},
  author       = {Van Maerken, Tom and Speleman, Franki and VERMEULEN, J and Lambertz, Irina and De Clercq, Sarah and De Smet, Els and Yigit, Nurten and COPPENS, V and Philipp{\'e}, Jan and De Paepe, Anne and Marine, Jean-Christophe and Vandesompele, Jo},
  issn         = {0008-5472},
  journal      = {CANCER RESEARCH},
  language     = {eng},
  number       = {19},
  pages        = {9646--9655},
  title        = {Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-06-0792},
  volume       = {66},
  year         = {2006},
}

Chicago
Van Maerken, Tom, Franki Speleman, J VERMEULEN, Irina Lambertz, Sarah De Clercq, Els De Smet, Nurten Yigit, et al. 2006. “Small-molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma.” Cancer Research 66 (19): 9646–9655.
APA
Van Maerken, T., Speleman, F., VERMEULEN, J., Lambertz, I., De Clercq, S., De Smet, E., Yigit, N., et al. (2006). Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. CANCER RESEARCH, 66(19), 9646–9655.
Vancouver
1.
Van Maerken T, Speleman F, VERMEULEN J, Lambertz I, De Clercq S, De Smet E, et al. Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. CANCER RESEARCH. 2006;66(19):9646–55.
MLA
Van Maerken, Tom, Franki Speleman, J VERMEULEN, et al. “Small-molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma.” CANCER RESEARCH 66.19 (2006): 9646–9655. Print.