ArticleNeuro-oncology2012
Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas.
Article in Neuro-oncology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Medulloblastoma response to mevalonate pathway inhibition is independent of p53 status.Biology direct · 2026Article
- Lipid nanomedicine simultaneously inhibits BRD4/PI3K and MDM2/XIAP signaling pathways for effective treatment of Medulloblastoma.Journal of controlled release : official journal of the Controlled Release Society · 2025Article
- Medulloblastoma and the DNA Damage Response.Frontiers in oncology · 2022Review
- mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma.JCI insight · 2021Article
- Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2021Article
- CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells.Cancers · 2021Article
- Targeting the medulloblastoma: a molecular-based approach.Acta bio-medica : Atenei Parmensis · 2020Review
- Simultaneous Examination of Cellular Pathways using Multiplex Hextuple Luciferase Assaying.Current protocols in molecular biology · 2020Article
- Examining multiple cellular pathways at once using multiplex hextuple luciferase assaying.Nature communications · 2019Article
- NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma.Cell death & disease · 2019Article
- p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma.Molecular cancer research : MCR · 2019Article
- Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.EMBO molecular medicine · 2017Article
- Article
- Low-dose Actinomycin-D treatment re-establishes the tumoursuppressive function of P53 in RELA-positive ependymoma.Oncotarget · 2016Article
- MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.Science translational medicine · 2016Article
- p53 and Meduloblastoma.Cold Spring Harbor perspectives in medicine · 2015Review
- The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells.The Journal of cell biology · 2015Article
- Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.The Journal of biological chemistry · 2015Article
- Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors.Oncotarget · 2015Article
- DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: the same outcome of treatment with different doses in sensitive cell lines.Oncology reports · 2015Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Medulloblastomas account for 20% of pediatric brain tumors. With an overall survival of 40%-70%, their treatment is still a challenge. The majority of medulloblastomas lack p53 mutations, but even in cancers retaining wild-type p53, the tumor surveillance function of p53 is inhibited by the oncoprotein MDM2. Deregulation of the MDM2/p53 balance leads to malignant transformation. Here, we analyzed MDM2 mRNA and protein expression in primary medulloblastomas and normal cerebellum and assessed the mutational status of p53 and MDM2 expression in 6 medulloblastoma cell lines. MDM2 expression was elevated in medulloblastomas, compared with cerebellum. Four of 6 medulloblastoma cell lines expressed wild-type p53 and high levels of MDM2. The tumor-promoting p53-MDM2 interaction can be inhibited by the small molecule, nutlin-3, restoring p53 function. Targeting the p53-MDM2 axis using nutlin-3 significantly reduced cell viability and induced either cell cycle arrest or apoptosis and expression of the p53 target gene p21 in these 4 cell lines. In contrast, DAOY and UW-228 cells harboring TP53 mutations were almost unaffected by nutlin-3 treatment. MDM2 knockdown in medulloblastoma cells by siRNA mimicked nutlin-3 treatment, whereas expression of dominant negative p53 abrogated nutlin-3 effects. Oral nutlin-3 treatment of mice with established medulloblastoma xenografts inhibited tumor growth and significantly increased survival. Thus, nutlin-3 reduced medulloblastoma cell viability in vitro and in vivo by re-activating p53 function. We suggest that inhibition of the MDM2-p53 interaction with nutlin-3 is a promising therapeutic option for medulloblastomas with functional p53 that should be further evaluated in clinical trials.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.