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Non-genotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma

Official URL:https://doi.org/10.1182/blood-2005-04-1489
PubMed:View item in PubMed
Creators Name:Stuehmer, T. and Chatterjee, M. and Hildebrandt, M. and Herrmann, P. and Gollasch, H. and Gerecke, C. and Theurich, S. and Cigliano, L. and Manz, R.A. and Daniel, P.T. and Bommert, K. and Vassilev, L.T. and Bargou, R.C.
Journal Title:Blood
Journal Abbreviation:Blood
Page Range:3609-3617
Date:4 August 2005
Keywords:Alkylating Antineoplastic Agents, Apoptosis, Tumor Cell Line, DNA Damage, Imidazoles, Melphalan, Multiple Myeloma, Mutagens, Piperazines, Protein Binding, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Stromal Cells, Tumor Suppressor Protein p53, Animals, Mice
Abstract: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.
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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