Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer
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Abstract
MDM2 oncoprotein binds directly to the p53 tumor suppressor and inhibits its function in cancers retaining wild-type p53. Blocking this interaction using small molecules is a promising approach to reactivate p53 function and is being pursued as a new anticancer strategy. The spiro-oxindole MI-43, a small-molecule inhibitor of the MDM2-p53 interaction, was designed and examined for its cellular mechanism of action and therapeutic potential in colon cancer. MI-43 binds to MDM2 protein with a Ki value of 18 nmol/L and is 300 times more potent than a native p53 peptide. MI-43 blocks the intracellular MDM2-p53 interaction and induces p53 accumulation in both normal and cancer cells, with wild-type p53 without causing p53 phosphorylation. Induction of p53 leads to modulation of the expression of p53 target genes, including up-regulation of p21 and MDM2 in normal primary human cells and in colon cancer cells with wild-type p53. Using HCT-116 isogenic colon cancer cell lines differing only in p53 status or RNA interference to knockdown expression of p53 in the RKO colon cancer cell line, we show that the cell growth inhibition and cell death induction by MI-43 is p53 dependent. Furthermore, induction of cell cycle arrest by MI-43 is dependent on p53 and p21. In normal cells, MI-43 induces cell cycle arrest but not apoptosis. This study suggests that p53 activation by a potent and specific spiro-oxindole MDM2 antagonist may represent a promising therapeutic strategy for the treatment of colon cancer and should be further evaluated in vivo and in the clinic. [Mol Cancer Ther 2008;7(6):1533–42]
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The cellular mechanism of p53 restoration by spiro-oxindoles agreed with in vitro biochemical binding assays demonstrating that these potent MDM2 antagonists are capable of inhibiting the MDM2-p53 interaction in cells.
“The cellular mechanism of p53 restoration by spiro-oxindoles agreed with in vitro biochemical binding assays demonstrating that these potent MDM2 antagonists are capable of inhibiting the MDM2-p53 interaction in cells [40].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [40]
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- Authors
- Shangary, S., Ding, K., Qiu, S., Nikolovska-Coleska, Z., Bauer, J. A., Liu, M., Wang, G., Lu, Y., McEachern, D., Bernard, D., Bradford, C. R., Carey, T. E., & Wang, S.
- Affiliations
- 1Comprehensive Cancer Center and Departments of
- University of Michigan (US)
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2008-06-01
- Volume
- 7
- Issue
- 6
- Pages
- 1533-1542
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC2494594
- OpenAlex
- W2123184912
- Cited by
- 91
- References
- 29
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 11 · 2013: 8 · 2012: 7
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA121279, P50CA069568, P30CA046592)
- 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, p53 reactivation, p53-MDM2 interaction, p21, cell cycle arrest, colon cancer, spirooxindoles, apoptosis, p53 target genes, HCT116 cells, RKO cells, p53-dependent cell death
- MeSH terms
- Antineoplastic Agents, Cell Cycle, Cell Survival, Colonic Neoplasms, Enzyme Activation, Humans, Indoles, Phosphoserine, Protein Binding, Spiro Compounds, Drug Design, Tumor Suppressor Protein p53, Apoptosis, Caspases, Mitochondrial Proteins, Cytochromes c, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-mdm2
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