ArticleOncogene2007
Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1.
Article in Oncogene, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 1 of them a synthesis that pooled it.
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Who cites it
78 citing papers in PubMed, 1 synthesis or guideline pooled it, 161 citations in OpenAlex.
- Gene translocations in musculoskeletal neoplasms.Clinical orthopaedics and related research · 2008Pooled it
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- Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- Targeting Cell Cycle Facilitates E1A-Independent Adenoviral Replication.Journal of virology · 2023Article
- Effects of wound dressing based on the combination of silver@curcumin nanoparticles and electrospun chitosan nanofibers on wound healing.Bioengineered · 2022Article
- A Quantitative Systems Approach to Define Novel Effects of Tumour p53 Mutations on Binding Oncoprotein MDM2.International journal of molecular sciences · 2021Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The roles and regulation of MDM2 and MDMX: it is not just about p53.Genes & development · 2021Review
- Design, Synthesis, and Biological Evaluation of Aromatic Amide-Substituted Benzimidazole-Derived Chalcones. The Effect of UpregulatingMolecules (Basel, Switzerland) · 2020Article
- SRSF2 Regulation ofMolecular cancer research : MCR · 2020Article
- Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.Scientific reports · 2019Article
- p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells.Nucleic acids research · 2017Article
- Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53.Oncogene · 2017Article
- The Role of MDM2 in Promoting Genome Stability versus Instability.International journal of molecular sciences · 2017Review
- Enhanced response of melanoma cells to MEK inhibitors following unbiased IGF-1R down-regulation.Oncotarget · 2017Article
- MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.Journal of hematology & oncology · 2017Review
- Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist.Journal of neurosurgery · 2017Article
- The role of p53 in cancer drug resistance and targeted chemotherapy.Oncotarget · 2017Review
18 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53-/- cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73alpha and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.
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