ArticleJournal of hematology & oncology2012
HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas.
Article in Journal of hematology & oncology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
- Targeting Hdm2 and Hdm4 in Anticancer Drug Discovery: Implications for Checkpoint Inhibitor Immunotherapy.Cells · 2024Review
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy.International journal of molecular sciences · 2022Article
- Article
- Nutlin-3, A p53-Mdm2 Antagonist for Nasopharyngeal Carcinoma Treatment.Mini reviews in medicinal chemistry · 2018Review
- The role of p53 in cancer drug resistance and targeted chemotherapy.Oncotarget · 2017Review
- Apoptotic pathways as a therapeutic target for colorectal cancer treatment.World journal of gastrointestinal oncology · 2016Review
- Article
- Major apoptotic mechanisms and genes involved in apoptosis.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- Targeting RING domains of Mdm2-MdmX E3 complex activates apoptotic arm of the p53 pathway in leukemia/lymphoma cells.Cell death & disease · 2015Article
- Ubiquitination in disease pathogenesis and treatment.Nature medicine · 2014Review
- Nature and importance of follicular lymphoma precursors.Haematologica · 2014Review
- Mitochondrial structure alteration in human prostate cancer cells upon initial interaction with a chemopreventive agent phenethyl isothiocyanate.Cancer cell international · 2014Article
- p53 abnormalities and potential therapeutic targeting in multiple myeloma.BioMed research international · 2014Review
- p53 Family and Cellular Stress Responses in Cancer.Frontiers in oncology · 2014Review
- Targeting MDM2-p53 interaction for cancer therapy: are we there yet?Current medicinal chemistry · 2014Review
- Targeting p53 by small molecules in hematological malignancies.Journal of hematology & oncology · 2013Review
- Article
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundLymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphocytes for its potential clinical use.
resultsPreclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2.
conclusionsOur data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance.
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