ArticleMolecular cancer therapeutics2015
Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 41 citations in OpenAlex.
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- The Interaction of Structural Analogues of Phenothiazines in p53-Dependent Cellular Signaling Pathways.ACS omega · 2026Article
- BNIP3 is a key driver of breast cancer progression and a novel glycolysis-regulating biomarker.Scientific reports · 2025Article
- Molecular targets and therapies associated with poor prognosis of triple‑negative breast cancer (Review).International journal of oncology · 2025Review
- Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer.International journal of molecular sciences · 2025Article
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Identification of a Group of Therapeutic Targets and Prognostic Biomarker for Triple Negative Breast Cancer.Advances in therapy · 2024Article
- Review
- Induction of synergistic apoptosis by tetramethoxystilbene and nutlin-3a in human cervical cancer cells.Toxicological research · 2022Article
- Applicability of Anticancer Drugs for the Triple-Negative Breast Cancer Based on Homologous Recombination Repair Deficiency.Frontiers in cell and developmental biology · 2022Article
- Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors.Cancers · 2021Review
- Murine Double Minute 2 Gene (Saudi journal of biological sciences · 2021Article
- Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions.American journal of cancer research · 2021Review
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- Model-based optimization of combination protocols for irradiation-insensitive cancers.Scientific reports · 2020Article
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- Design, Synthesis, and Biological Evaluation of Aromatic Amide-Substituted Benzimidazole-Derived Chalcones. The Effect of UpregulatingMolecules (Basel, Switzerland) · 2020Article
- Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association.Breast cancer research : BCR · 2019Article
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
- The Role of MDM2 in Promoting Genome Stability versus Instability.International journal of molecular sciences · 2017Review
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Authors and funding
24 authors at 6 institutions in 2 countries.
Funding
Abstract
Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.
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