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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4300-4308. Prepublished online as a Blood First Edition Paper on February 3, 2009; DOI 10.1182/blood-2008-11-187708. This Article Full Text (PDF) All Versions of this Article: blood-2008-11-187708v1 113/18/4300    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 Secchiero, P. Articles by Zauli, G. Search for Related Content PubMed PubMed Citation Articles by Secchiero, P. Articles by Zauli, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 5, 2008 Accepted January 23, 2009 Nutlin-3 upregulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feed-back anti-apoptotic mechanism Paola Secchiero*, Elisabetta Melloni, Maria Grazia di Iasio, Mario Tiribelli, Erika Rimondi, Federica Corallini, Valter Gattei, and Giorgio Zauli Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy Department of Medical and Morphological Research, Division of Hematology and Bone Marrow Transplantation, University Hospital, Udine, Italy Clinical and Experimental Hematology Research Unit, Centro di Riferimento Oncologico, I.R.C.C.S, Aviano (PN), Italy * Corresponding author; email: paola.secchiero{at}unife.it. The small molecule inhibitor of the MDM2/p53 interaction Nutlin-3 significantly up-regulated the steady-state mRNA and protein levels of Notch1 in p53wild-type (OCI, SKW6.4) but not in p53deleted (HL-60) or p53mutated (BJAB) leukemic cell lines. A direct demonstration that Notch1 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53. Moreover, inhibition of Notch1 expression by using Notch1 specific siRNA significantly increased cytotoxicity in p53wild-type leukemic cells. Of note, Nutlin-3 up-regulated Notch1 expression also in primary p53wild-type B-chronic lymphocytic leukemia (B-CLL) cells and the combined use of Nutlin-3 plus pharmacological -secretase inhibitors of the Notch signaling, showed a synergistic cytotoxicity in both p53wild-type leukemic cell lines and primary B-CLL. A potential drawback of -secretase inhibitors was their ability to enhance osteoclastic maturation of normal circulating preosteoclasts induced by RANKL+M-CSF. Notwithstanding, Nutlin-3 completely suppressed osteoclastogenesis irrespective of the presence of -secretase inhibitors. Taken together, these data indicate that the p53-dependent up-regulation of Notch1 in response to Nutlin-3 represents an anti-apoptotic feed-back mechanism able to restrain the potential therapeutic efficacy of Nutlin-3 in hematological malignancies. Therefore, therapeutic combinations of Nutlin-3+-secretase inhibitors might potentiate the cytotoxicity of Nutlin-3 in p53wild-type leukemic cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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]

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