A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis
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Abstract
The p53 inactivation caused by aberrant expression of its major regulators (e.g., MDM2 and MDMX) contributes to the genesis of a large number of human cancers. Recent studies have shown that restoration of p53 activity by counteracting p53 repressors is a promising anticancer strategy. Although agents (e.g., nutlin-3a) that disrupt MDM2–p53 interaction can inhibit tumor growth, they are less effective in cancer cells that express high levels of MDMX. MDMX binds to p53 and can repress the tumor suppressor function of p53 through inhibiting its trans-activation activity and/or destabilizing the protein. Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. Treatments of MCF-7 cells with this small-molecule MDMX inhibitor activated p53, resulting in elevated expression of proapoptotic genes (e.g., PUMA, BAX, and PIG3). Importantly, this novel small-molecule p53 activator caused MCF-7 cells to undergo apoptosis and acted additively with nutlin-3a to activate p53 and decrease the viability of cancer cells. These results thus show that small molecules targeting MDMX expression would be of therapeutic benefits. Mol Cancer Ther; 10(1); 69–79. ©2010 AACR.
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A benzofuroxan derivative (NSC207895) selectively inhibits MDMX expression, downregulates MDMX levels and causes p53-dependent transactivation of proapoptotic genes in several cancer cell lines.
“A benzofuroxan derivative (NSC207895) that selectively inhibits MDMX expression has been identified88. This molecule downregulates MDMX levels and causes p53-dependent transactivation of proapoptotic genes in several cancer cell lines.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [88]
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- Authors
- Wang, H., Ma, X., Ren, S., Buolamwini, J. K., & Yan, C.
- Affiliations
- University of Tennessee Health Science Center (US)
- Corresponding author
- Yan, Chunhong
- Venue
- Molecular Cancer Therapeutics
- Published
- 2011-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 69-79
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC3058295
- OpenAlex
- W2111796766
- Cited by
- 117
- References
- 54
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 14 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 7 · 2014: 10 · 2013: 10 · 2012: 12
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA139107)
- 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
- MDMX, p53 activation, small molecule inhibitors, apoptosis, Nutlin-3a, p53-MDM2 interaction, breast cancer cells, MCF-7 cells, PUMA, Bax, PIG3
- MeSH terms
- Antineoplastic Agents, Breast Neoplasms, Cell Survival, Drug Screening Assays, Antitumor, Humans, Nuclear Proteins, Oxadiazoles, Phosphorylation, Piperazines, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transfection, Tumor Suppressor Protein p53, Apoptosis, Cell Cycle Proteins, Cell Line, Tumor, Gene Knockdown Techniques
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