MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
These findings suggest that the MDM2 antagonist Nutlin-3 may be an effective agent in the treatment of MCL with or without wt-TP53.
Tabe
Yoko
Y
Hematopathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Sebasigari
Denise
D
Jin
Linhua
L
Rudelius
Martina
M
Davies-Hill
Theresa
T
Miyake
Kazunori
K
Miida
Takashi
T
Pittaluga
Stefania
S
Raffeld
Mark
M
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D001897:Boronic Acids; D018797:Cell Cycle Proteins; D007093:Imidazoles; C482775:MDM4 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C482205:nutlin 3; D000069286:Bortezomib; D004317:Doxorubicin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D055372:AMP-Activated Protein Kinases; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase