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Blood, 15 May 2006, Vol. 107, No. 10, pp. 4109-4114. Prepublished online as a Blood First Edition Paper on January 26, 2006; DOI 10.1182/blood-2005-08-3273. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2005-08-3273v1 107/10/4109    most recent Alert me when this article is cited Alert me if a correction is posted 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 Coll-Mulet, L. Articles by Gil, J. Search for Related Content PubMed PubMed Citation Articles by Coll-Mulet, L. Articles by Gil, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 12, 2005 Accepted January 12, 2006 MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells Llorenc Coll-Mulet, Daniel Iglesias-Serret, Antonio F Santidrian, Ana M Cosialls, Merce de Frias, Esther Castano, Clara Campas, Montserrat Barragan, Alberto Fernandez de Sevilla, Alicia Domingo, Lyubomir T Vassilev, Gabriel Pons, and Joan Gil* Departament de Ciencies Fisiologiques II, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain Departament d'Hematologia Clinica, IDIBELL-Institut Catala d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain Servei d'Hematologia, IDIBELL-Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey, USA * Corresponding author; email: jgil{at}ub.edu. B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5+ B lymphocytes. Several drugs currently used in the therapy of B-CLL act, at least partially, through activation of the p53 pathway. Recently, non-genotoxic small-molecule activators of p53, the nutlins, have been developed that inhibit p53-MDM2 binding. We have investigated the antitumor potential of nutlin-3 in B-CLL and find that it can activate the p53 pathway and effectively induce apoptosis in cells with wild-type p53, including cells with dysfunctional ATM, but not mutant p53. Nutlin-3 stabilized p53 and induced p53 target genes including MDM2, p21, PUMA, Bax, PIG3 and WIG1. Nutlin-3 synergized with the genotoxic drugs doxorubicin, chlorambucil, and fludarabine but not with acadesine, which induces p53-independent apoptosis. Normal human T cells showed lower sensitivity to nutlin-3 than B-CLL cells and no synergism with the genotoxic drugs. These results suggest that MDM2 antagonists alone or in combination with chemotherapeutic drugs may offer a new treatment option for B-CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Roberts, I. R. Watson, A. J. Evans, D. A. Foster, M. S. Irwin, and M. Ohh Suppression of Hypoxia-Inducible Factor 2{alpha} Restores p53 Activity via Hdm2 and Reverses Chemoresistance of Renal Carcinoma Cells Cancer Res., December 1, 2009; 69(23): 9056 - 9064. [Abstract] [Full Text] [PDF] T. Van Maerken, L. Ferdinande, J. Taildeman, I. Lambertz, N. Yigit, L. Vercruysse, A. Rihani, M. Michaelis, J. Cinatl Jr, C. A. Cuvelier, et al. Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53 J Natl Cancer Inst, November 18, 2009; 101(22): 1562 - 1574. [Abstract] [Full Text] [PDF] L. Caja, P. Sancho, E. Bertran, D. Iglesias-Serret, J. Gil, and I. 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