BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death
Open accessAbstract
The Hdmx protein restricts p53 activity in vivo and is overexpressed in a significant fraction of human tumors that retain the wild type p53 allele. An understanding of how Hdmx limits p53 activation and blocks apoptosis could therefore lead to development of novel therapeutic agents. We previously showed that Hdmx modulates tumor cell sensitivity to Nutlin-3a, a potent antagonist of the p53/Hdm2 interaction. In this report, we demonstrate that this also applies to MI-219, another Hdm2 antagonist. Thus, the inability to disrupt Hdmx/p53 complexes is a potential barrier to the efficacy of these compounds as single agents. We show that sensitivity to apoptosis in cells with high Hdmx levels is restored by combined treatment with Nutlin and a Bcl-2 family member antagonist to activate Bax. The data are consistent with a model in which Hdmx attenuates p53-dependent activation of the intrinsic apoptotic pathway, and that this occurs upstream of Bax activation. Thus, selectively inhibiting Hdm2 and activating Bax is one effective strategy to induce apoptosis in tumors with high Hdmx levels. Our findings also indicate that preferential induction of apoptosis in tumor versus normal cells occurs using appropriate drug doses.
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Mdmx was shown to prevent p53-dependent activation of bax and consequently apoptosis in a previous study.
“Indeed, Mdmx was shown to prevent p53-dependent activation of bax, and consequently apoptosis, in a previous study [115].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [115]
Nutlin 3a and MI-219 robustly activate p53 in cancer cells with overexpressed MDM2, but do not consistently elicit p53-dependent effects in cancer cells that overexpress MDMX.
“Although nutlin 3a and MI-219 robustly activate p53 in cancer cells with overexpressed MDM2, they do not consistently elicit p53-dependent effects in cancer cells that overexpress MDMX99–102.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [100]
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- Authors
- Wade, M., Rodewald, L. W., Espinosa, J. M., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2008-07
- Volume
- 7
- Issue
- 13
- Pages
- 1973-1982
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC2625302
- OpenAlex
- W1494333095
- Cited by
- 48
- References
- 48
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 6 · 2015: 1 · 2014: 6 · 2013: 1 · 2012: 7
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Clinical Cancer Research
- Funders
- Abbott Laboratories
- National Institutes of Health
- National Cancer Institute (CA61449, R01CA061449, R01CA117907, CA117907)
- 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
- HDMX, p53, Nutlin-3a, BH3 mimetics, Bax activation, apoptosis, mitochondrial apoptosis, p53-MDM2 interaction, tumor cell sensitivity, combination therapy, selective tumor cell killing
- MeSH terms
- Biphenyl Compounds, Cell Cycle, Humans, Imidazoles, Nitrophenols, Nuclear Proteins, Piperazines, Proto-Oncogene Proteins, Sulfonamides, Down-Regulation, Tumor Suppressor Protein p53, Apoptosis, Cell Cycle Proteins, Proto-Oncogene Proteins c-bcl-2, Cell Line, Tumor, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
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