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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2450-2462. Prepublished online as a Blood First Edition Paper on June 26, 2008; DOI 10.1182/blood-2007-10-114348. This Article Full Text Full Text (PDF) Supplemental Methods and Figure All Versions of this Article: blood-2007-10-114348v1 112/6/2450    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 CrossRef Google Scholar Articles by Lunghi, P. Articles by Bonati, A. PubMed PubMed Citation Articles by Lunghi, P. Articles by Bonati, A. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Paolo Lunghi1, Nicola Giuliani2, Laura Mazzera1, Guerino Lombardi3, Micaela Ricca3, Attilio Corradi4, Anna Maria Cantoni4, Luigi Salvatore1, Roberta Riccioni5, Antonio Costanzo6, Ugo Testa5, Massimo Levrero7,8, Vittorio Rizzoli2, and Antonio Bonati1,2 1 Department of Clinical Sciences, University of Parma, Parma; 2 Unit of Hematology and Bone Marrow Transplantation, University Hospital of Parma, Parma; 3 Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna Bruno Ubertini, Brescia; 4 Department of Animal Health, Pathology Unit, Faculty of Veterinary Medicine, University of Parma, Parma; 5 Department of Hematology, Oncology and Molecular Medicine, Italian Institute of Public Health, Rome; 6 Department of Dermatology, University of Rome Tor Vergata, Rome; 7 Department of Internal Medicine, University of Rome La Sapienza, Rome; and 8 Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza, Rome, Italy We demonstrate that blockade of the MEK/ERK signaling module, using the small-molecule inhibitors PD184352 or PD325901 (PD), strikingly enhances arsenic trioxide (ATO)–induced cytotoxicity in human myeloma cell lines (HMCLs) and in tumor cells from patients with multiple myeloma (MM) through a caspase-dependent mechanism. In HMCLs retaining a functional p53, PD treatment greatly enhances the ATO-induced p53 accumulation and p73, a p53 paralog, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a nonfunctional p53, cotreatment with PD strikingly elevates the (DR4 + DR5)/(DcR1 + DcR2) tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) receptors ratio and caspase-8 activation of ATO-treated cells. In MM cells, irrespective of p53 status, the combined PD/ATO treatment increases the level of the proapoptotic protein Bim (PD-mediated) and decreases antiapoptotic protein Mcl-1 (ATO-mediated). Moreover, Bim physically interacts with both DR4 and DR5 TRAIL receptors in PD/ATO-treated cells, and loss of Bim interferes with the activation of both extrinsic and intrinsic apoptotic pathways in response to PD/ATO. Finally, PD/ATO treatment induces tumor regression, prolongs survival, and is well tolerated in vivo in a human plasmacytoma xenograft model. These preclinical studies provide the framework for testing PD325901 and ATO combination therapy in clinical trials aimed to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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