The DOI matches its Crossref record; 36 of the 38 references it cites were found in a registry or an index.
Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Although it has been shown that nutlin3a and other MDM2 PPI inhibitors have single-agent activity in inhibiting the growth of a variety of tumor types including GBM”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [2]
In the citing paper
“The MDM2 protein–protein interaction (PPI) inhibitor nutlin3a binds to the N-terminal hydrophobic pocket of MDM2 and blocks interaction of MDM2 with not only p53 but also a number of other key signal transducers, including p73α, E2F1, Rb, and HIF-1α”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [2]
In the citing paper
“Nutlin-3a also inhibits the binding of the p73 isoform p73α, as well as E2F1 and hypoxia inducible factor 1α (Hif-1α), to the N-terminal hydrophobic pocket of Mdm2 (11–13).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [11]
Citations
Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Self-citationThe MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982
Expression of transcription factor E2F1 induces quiescent cells to enter S phase
Johnson, D. G., Schwarz, J. K., Cress, W. D., & Nevins, J. R. (1993) · Nature · doi:10.1038/365349a0 · Cited by 943
p53 and E2F-1 cooperate to mediate apoptosis.
Wu, X., & Levine, A. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.9.3602 · Cited by 840
Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.
Qin, X. Q., Livingston, D. M., Kaelin, W. G., & Adams, P. D. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10918 · Cited by 753
Müller, H., Bracken, A. P., Vernell, R., Moroni, M. C., Christians, F. C., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J. D., & Helin, K. (2001) · Genes & Development · doi:10.1101/gad.864201 · Cited by 752
Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53
Honda, R., & Yasuda, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.1.22 · Cited by 724
Role for the p53 homologue p73 in E2F-1-induced apoptosis
Irwin, M. S., Marín, M. C., Phillips, A. C., Seelan, R. S., Smith, D. I., Liu, W., Flores, E. R., Tsai, K. Y., Jacks, T., Vousden, K. H., et al. (2000) · Nature · doi:10.1038/35036614 · Cited by 710
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507493103 · Cited by 708
Self-citationInteraction between the retinoblastoma protein and the oncoprotein MDM2
Xiao, Z.-X., Chen, J., Levine, A. J., Modjtahedi, N., Xing, J. W., Sellers, W. R., & Livingston, D. M. (1995) · Nature · doi:10.1038/375694a0 · Cited by 586
Research works printed but not linked: 1
- Banerjee D, Schnieders B, Fu JZ, Adhikari D, Zhao SC, Bertino JR . (1998). Role of E2F1 in chemosensitivity. Cancer Res 58: 4292–4296.
Cited by
Sorted by citations
Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy
Barretina, J., Taylor, B. S., Banerji, S., Ramos, A. H., Lagos-Quintana, M., DeCarolis, P. L., Shah, K., Socci, N. D., Weir, B. A., Ho, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.619 · Cited by 735
Self-citationThe role of p53 in cancer drug resistance and targeted chemotherapy
Hientz, K., Mohr, A., Bhakta-Guha, D., & Efferth, T. (2016) · Oncotarget · doi:10.18632/oncotarget.13475 · Cited by 612
p53 and E2f: partners in life and death
Polager, S., & Ginsberg, D. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2718 · Cited by 498
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 372
Metadata
- Authors
- Ambrosini, G., Sambol, E. B., Carvajal, D., Vassilev, L. T., Singer, S., & Schwartz, G. K.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Schwartz, G K
- Venue
- Oncogene
- Published
- 2006-12-04
- Volume
- 26
- Issue
- 24
- Pages
- 3473-3481
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2003463790
- Cited by
- 163
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 8 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 7 · 2018: 1 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 13 · 2013: 11 · 2012: 15
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- Nutlin-3a, MDM2 inhibitors, mutant p53, E2F1, chemotherapy-induced apoptosis, cisplatin, chemosensitization, malignant peripheral nerve sheath tumor, liposarcoma, p73alpha, Noxa, proteasomal degradation, p53-MDM2 interaction, doxorubicin, carboplatin
- MeSH terms
- Tumor Protein p73, Animals, Antineoplastic Agents, Cisplatin, DNA-Binding Proteins, Doxorubicin, Humans, Imidazoles, Nuclear Proteins, Piperazines, Transcription, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Carboplatin, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Proteins, E2F1 Transcription Factor, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
