MDM2 Antagonist Nutlin-3 Displays Antiproliferative and Proapoptotic Activity in Mantle Cell Lymphoma
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Purpose: Mantle cell lymphoma (MCL) has one of the poorest prognoses of the non-Hodgkin's lymphomas, and novel therapeutic approaches are needed. We wished to determine whether Nutlin-3, a novel small-molecule murine double minute 2 (MDM2) antagonist that efficiently activates TP53, might be effective in inducing cell death in MCL. Experimental Design: MCL cell lines with known TP53 status were treated with Nutlin-3, and biological and biochemical consequences were studied. Synergies with the prototypic genotoxic agent doxorubicin and the novel proteasome inhibitor bortezomib were assessed. Results: Nutlin-3 resulted in a reduction in cell proliferation/viability (IC50 < 10 μmol/L), an increase in the apoptotic fraction, and cell cycle arrest in wild-type (wt) TP53 Z-138 and Granta 519 cells. These effects were accompanied by TP53 accumulation and induction of TP53-dependent proteins p21, MDM2, Puma, and Noxa. Cell cycle arrest was characterized by suppression of S phase and an increase in the G0-G1 and G2-M fractions and accompanied by suppression of total and phosphorylated retinoblastoma protein and a decrease in G2-M-associated proteins cyclin B and CDC2. The combination of Nutlin-3 with doxorubicin or bortezomib was synergistic in wt-TP53 MCL cells. Nutlin-3 also induced cell cycle arrest and reduced cell viability in the mutant TP53 MINO cells but at a significantly higher IC50 (22.5 μmol/L). These effects were associated with induction of the TP53 homologue p73, slight increases in p21 and Noxa, and caspase activation. Nutlin-3 and bortezomib synergistically inhibited cell growth of MINO. Conclusion: These findings suggest that the MDM2 antagonist Nutlin-3 may be an effective agent in the treatment of MCL with or without wt-TP53.
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Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists.
“Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists75,76.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [76]
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References 62 · Cited by 83
- Authors
- Tabe, Y., Sebasigari, D., Jin, L., Rudelius, M., Davies-Hill, T., Miyake, K., Miida, T., Pittaluga, S., & Raffeld, M.
- Affiliations
- National Institutes of Health (US)
- Juntendo University (JP)
- Venue
- Clinical Cancer Research
- Published
- 2009-02-01
- Volume
- 15
- Issue
- 3
- Pages
- 933-942
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7322626
- OpenAlex
- W2108483542
- Cited by
- 83
- References
- 62
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 1 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 9 · 2012: 9
- FWCI
- 6.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC011079)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- Nutlin-3, MDM2 inhibitors, mantle cell lymphoma, TP53, apoptosis, cell cycle arrest, p73, p21, bortezomib, doxorubicin, drug synergy, retinoblastoma protein, cyclin B, cdc2, caspase activation, TP53 mutation
- MeSH terms
- Bortezomib, Tuberous Sclerosis Complex 2 Protein, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Cell Cycle, Doxorubicin, Humans, Imidazoles, Membrane Proteins, Nuclear Proteins, Piperazines, Proto-Oncogene Proteins, Pyrazines, Tumor Suppressor Protein p53, Apoptosis, Cell Cycle Proteins, Lymphoma, Mantle-Cell, Tumor Suppressor Proteins, Cell Line, Tumor, Cell Proliferation, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-mdm2, AMP-Activated Protein Kinases
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