ArticleMolecular cancer research : MCR2015
Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
Article in Molecular cancer research : MCR, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- Article
- Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer.Cancer discovery · 2023Article
- DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.Cancers · 2023Review
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- DNA double-strand breaks repair inhibitors potentiates the combined effect of VP-16 and CDDP in human colorectal adenocarcinoma (LoVo) cells.Molecular biology reports · 2021Article
- Cisplatin in Combination with MDM2 Inhibition Downregulates Rad51 Recombinase in a Bimodal Manner to Inhibit Homologous Recombination and Augment Tumor Cell Kill.Molecular pharmacology · 2020Article
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
- Loss of p53 expression in cancer cells alters cell cycle response after inhibition of exportin-1 but does not prevent cell death.Cell cycle (Georgetown, Tex.) · 2018Article
- Effect of etoposide-induced alteration of the Mdm2-Rb signaling pathway on cellular senescence in A549 lung adenocarcinoma cells.Oncology letters · 2017Article
- Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells.Cancer research · 2017Article
- Role of Mdm2 and Mdmx in DNA repair.Journal of molecular cell biology · 2017Review
- TP53 mutations in epithelial ovarian cancer.Translational cancer research · 2016Article
- Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia.Oncotarget · 2016Article
- Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2016Article
- Genome Stability Requires p53.Cold Spring Harbor perspectives in medicine · 2016Review
- Clinical Overview of MDM2/X-Targeted Therapies.Frontiers in oncology · 2016Review
- Investigation of the Effects of Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) on Apoptosis and Cell Cycle in a Zebrafish (Danio rerio) Liver Cell Line.International journal of environmental research and public health · 2015Article
- Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model.Molecular cancer therapeutics · 2015Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledThe Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2-p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11-Rad50-Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53. IMPLICATIONS: Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.
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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.