Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma.
Mutation of p53 is a rare event in multiple myeloma, but it is unknown if p53 signaling is functional in myeloma cells, and if targeted nongenotoxic activation of the p53 pathway is sufficient to kill tumor cells. Here, we demonstrate that treatment of primary tumor samples with a small-molecule inhibitor of the p53-murine double minute 2 (MDM2) interaction increases the level of p53 and induces p53 targets and apoptotic cell death. Significantly, given the importance of the bone marrow microenvironment for the support and drug resistance of myeloma cells, tumor cells undergo effective apoptosis also in the presence of stromal cells, which themselves appear to tolerate exposure to nutlin-3. The in vitro toxicity of nutlin-3 was similar to that of the genotoxic drug melphalan. Because nutlin-mediated p53 activation is not dependent on DNA damage, MDM2 antagonists may help to avoid or reduce the severe genotoxic side effects of chemotherapeutic agents currently used to treat multiple myeloma. Therefore, MDM2 antagonists may offer a new treatment option for this disease.
Stühmer
Thorsten
T
Department of Internal Medicine II, Division of Hematology and Oncology, University Clinics Würzburg, Germany. stuhmer@web.de
Chatterjee
Manik
M
Hildebrandt
Martin
M
Herrmann
Pia
P
Gollasch
Hella
H
Gerecke
Christian
C
Theurich
Sebastian
S
Cigliano
Luisa
L
Manz
Rudolf A
RA
Daniel
Peter T
PT
Bommert
Kurt
K
Vassilev
Lyubomir T
LT
Bargou
Ralf C
RC
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008558:Melphalan / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009153:Mutagens / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D009153:Mutagens; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D008558:Melphalan