The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy
Abstract
The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo , suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53–MDM2 interaction.
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In the citing paper
“Restoration of p53 is known to block cell-cycle progression and induces apoptosis in the presence of MDM2-p53 interaction antagonists [43–45].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [43]
In the citing paper
“the MDM2 antagonist nutlin 3a (discussed below) is well-tolerated in mouse preclinical models84.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [84]
In the citing paper
“Nutlin profoundly decreased the viability of SJSA cells, as reported previously26”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [26]
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Metadata
- Authors
- Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., Myklebost, O., Heimbrook, D. C., & Vassilev, L. T.
- Affiliations
- *Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and
- F. Hoffmann-La Roche AG (CH)
- Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-01-27
- Volume
- 103
- Issue
- 6
- Pages
- 1888-1893
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1993263392
- Cited by
- 708
- References
- 36
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 15 · 2023: 39 · 2022: 23 · 2021: 27 · 2020: 25 · 2019: 33 · 2018: 20 · 2017: 27 · 2016: 44 · 2015: 39 · 2014: 45 · 2013: 39 · 2012: 47
- FWCI
- 25.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MDM2 inhibitors, Nutlin-3, p53 pathway, p53-dependent apoptosis, cell cycle arrest, MDM2 amplification, p53-MDM2 interaction, apoptosis-related gene expression, cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Cell Cycle, Cell Line, Humans, Imidazoles, Mice, Nude, Neoplasms, Piperazines, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Gene Expression Profiling, Xenograft Model Antitumor Assays, Mice, Proto-Oncogene Proteins c-mdm2
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