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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 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 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 Coll-Mulet, L. Articles by Gil, J. Search for Related Content PubMed PubMed Citation Articles by Coll-Mulet, L. Articles by Gil, J. Related Collections Immunobiology Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells Llorenç Coll-Mulet, Daniel Iglesias-Serret, Antonio F. Santidrián, Ana M. Cosialls, Mercè de Frias, Esther Castaño, Clara Campàs, Montserrat Barragán, Alberto Fernández de Sevilla, Alicia Domingo, Lyubomir T. Vassilev, Gabriel Pons, and Joan Gil From the Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Departament d'Hematologia Clínica, IDIBELL–Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain; Servei d'Hematologia, IDIBELL–Hospital de Bellvitge, L'Hospitalet de Llobregat, Spain; and Discovery Oncology, Roche Research Center, Hoffmann–La Roche, Inc, Nutley, NJ. 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, nongenotoxic 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 ataxia telangiectasia mutated, but not mutant p53. Nutlin-3 stabilized p53 and induced p53 target genes, including MDM2, p21CIP1, 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: I. Seyfried, S. Hofbauer, M. Stoecher, R. Greil, and I. Tinhofer SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a Blood, September 1, 2008; 112(5): 2168 - 2168. [Full Text] [PDF] K. Kumamoto, E. A. Spillare, K. Fujita, I. Horikawa, T. Yamashita, E. Appella, M. Nagashima, S. Takenoshita, J. Yokota, and C. C. Harris Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence Cancer Res., May 1, 2008; 68(9): 3193 - 3203. [Abstract] [Full Text] [PDF] N. Zhu, L. Gu, F. Li, and M. Zhou Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1101 - 1109. [Abstract] [Full Text] [PDF] P. Secchiero, E. Melloni, M. Tiribelli, A. Gonelli, and G. Zauli Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells J. Leukoc. 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