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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4549-4553. Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-07-2829. This Article Full Text (PDF) All Versions of this Article: 2005-07-2829v1 107/11/4549    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 Lunghi, P. Articles by Bonati, A. Search for Related Content PubMed PubMed Citation Articles by Lunghi, P. Articles by Bonati, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 15, 2005 Accepted January 21, 2006 MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis Paolo Lunghi, Antonio Costanzo, Luigi Salvatore, Nelida Noguera, Laura Mazzera, Antonio Tabilio, Francesco Lo-Coco, Massimo Levrero, and Antonio Bonati* Department of Clinical Sciences, Section of Hemato-Oncology, University of Parma, Parma, Italy Department of Dermatology, University of Rome "Tor Vergata", Rome, Italy; Rome Oncogenomic Center (ROC), Rome, Italy Department of Biopathology, Section of Hematology, University of Rome "Tor Vergata", Rome, Italy Department of Clinical and Experimental Medicine, Section of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy Department of Internal Medicine, and Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome "Tor Vergata", Rome, Italy; Department of Experimental Oncology, CRS-Regina Elena Cancer Institute, Rome, Italy; Rome Oncogenomic Center (ROC), Rome, Italy * Corresponding author; email: antbonny{at}unipr.it. We have found that MEK1 inhibitor PD184352 strikingly increases apoptosis induced by Arsenic Trioxide (ATO) in twenty-one out of twenty-five primary acute myelogenous leukemia (AML) cases. Isobologram analysis confirmed the synergistic (13/25 cases) or additive (8/25 cases) nature of this interaction. Moreover we demonstrate that the p53-related gene p73 is a molecular target of the combined treatment in AML blasts. Indeed, ATO modulates the expression of the p73 gene by inducing both the pro-apoptotic and anti-proliferative TAp73 and the anti-apoptotic and pro-proliferative Np73 isoforms thereby failing to elevate TA/Np73 ratio. Conversely the treatment with PD184352 reduces the level of Np73 and blunts the arsenic-mediated up-regulation of Np73, thus causing a raise of the TA/Np73 ratio of dual-treated cells. Moreover, high doses of ATO induce p53 accumulation in 11/21 cases. Combined treatment results in the induction of the proapoptotic p53/p73-target gene p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), and greatly enhances apoptosis of treated cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Lunghi, A. Costanzo, L. Mazzera, V. Rizzoli, M. Levrero, and A. Bonati The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting Clin. Cancer Res., November 1, 2009; 15(21): 6495 - 6502. [Abstract] [Full Text] [PDF] L. C. Platanias Biological Responses to Arsenic Compounds J. Biol. Chem., July 10, 2009; 284(28): 18583 - 18587. [Abstract] [Full Text] [PDF] P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF] B. C. Bornhauser, L. Bonapace, D. Lindholm, R. Martinez, G. Cario, M. Schrappe, F. K. Niggli, B. W. Schafer, and J.-P. Bourquin Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway Blood, September 15, 2007; 110(6): 2084 - 2091. [Abstract] [Full Text] [PDF] G. S. Dbaibo, Y. Kfoury, N. Darwiche, S. Panjarian, L. Kozhaya, R. Nasr, M. Abdallah, O. Hermine, M. El-Sabban, H. de The, et al. Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity Haematologica, June 1, 2007; 92(6): 753 - 762. [Abstract] [Full Text] [PDF] C. Bozzetti, R. Nizzoli, A. Musolino, E. M. Martella, P. Crafa, C. A. Lagrasta, R. Camisa, A. Bonati, P. Lunghi, and A. Ardizzoni p73 and p53 Pathway in Human Breast Cancers J. Clin. Oncol., April 10, 2007; 25(11): 1451 - 1453. [Full Text] [PDF] P. Lunghi, L. Mazzera, V. Rizzoli, and A. Bonati Mdm2 Inhibitor Nutlin-3 Enhances the Cytotoxic Synergism Induced by the Combination of MEK1 Inhibitor and Arsenic Trioxide (ATO) in AML Cells. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1364 - 1364. [Abstract] [PDF]

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