Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma.
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 wild-type 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 pleiotropic 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.
Van Maerken
Tom
T
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. tom.vanmaerken@UGent.be
Speleman
Frank
F
Vermeulen
Joëlle
J
Lambertz
Irina
I
De Clercq
Sarah
S
De Smet
Els
E
Yigit
Nurten
N
Coppens
Vicky
V
Philippé
Jan
J
De Paepe
Anne
A
Marine
Jean-Christophe
JC
Vandesompele
Jo
J
D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects; D018628:Gene Dosage; D018390:Gene Targeting; D016259:Genes, myc; D016158:Genes, p53; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009447:Neuroblastoma / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D007093:Imidazoles; D009363:Neoplasm Proteins; D010879:Piperazines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2