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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3609-3617. Prepublished online as a Blood First Edition Paper on August 4, 2005; DOI 10.1182/blood-2005-04-1489. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-04-1489v1 106/10/3609    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stühmer, T. Articles by Bargou, R. C. Search for Related Content PubMed PubMed Citation Articles by Stühmer, T. Articles by Bargou, R. C. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma Thorsten Stühmer, Manik Chatterjee, Martin Hildebrandt, Pia Herrmann, Hella Gollasch, Christian Gerecke, Sebastian Theurich, Luisa Cigliano, Rudolf A. Manz, Peter T. Daniel, Kurt Bommert, Lyubomir T. Vassilev, and Ralf C. Bargou From the Department of Internal Medicine II, Division of Hematology and Oncology, University Clinics Würzburg, Würzburg, Germany; the Department of Hematology, Oncology, and Tumorimmunology, Robert Rössle Cancer Clinic at the Max Delbrück Center for Molecular Medicine, Charité-Berlin University Medicine, Campus Buch, Berlin, Germany; Discovery Oncology, Hoffmann-La Roche, Nutley, NJ; and Department of Humoral Immunology, German Rheumatism Research Center, Berlin, Germany. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Miyachi, N. Kakazu, S. Yagyu, Y. Katsumi, S. Tsubai-Shimizu, K. Kikuchi, K. Tsuchiya, T. Iehara, and H. Hosoi Restoration of p53 Pathway by Nutlin-3 Induces Cell Cycle Arrest and Apoptosis in Human Rhabdomyosarcoma Cells Clin. Cancer Res., June 15, 2009; 15(12): 4077 - 4084. [Abstract] [Full Text] [PDF] P. Secchiero, E. Melloni, M. G. di Iasio, M. Tiribelli, E. Rimondi, F. Corallini, V. Gattei, and G. 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