Login
- Title:
MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma.
- Document type:
- Journal Article
- Author(s):
- Tabe, Y; Sebasigari, D; Jin, L; Rudelius, M; Davies-Hill, T; Miyake, K; Miida, T; Pittaluga, S; Raffeld, M
- Abstract:
- 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 micromol/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 micromol/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.
- Journal title abbreviation:
- Clin Cancer Res
- Year:
- 2009
- Journal volume:
- 15
- Journal issue:
- 3
- Pages contribution:
- 933-42
- Language:
- eng
- Fulltext / DOI:
- doi:10.1158/1078-0432.CCR-08-0399
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/19188164
- Print-ISSN:
- 1078-0432
- TUM Institution:
- Institut für Allgemeine Pathologie und Pathologische Anatomie
BibTeX