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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.
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Submitted October 3, 2007
Accepted June 12, 2008
Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways
Paolo Lunghi*, Nicola Giuliani, Laura Mazzera, Guerino Lombardi, Micaela Ricca, Attilio Corradi, Anna Maria Cantoni, Luigi Salvatore, Roberta Riccioni, Antonio Costanzo, Ugo Testa, Massimo Levrero, Vittorio Rizzoli, and Antonio Bonati
Department of Clinical Sciences, University of Parma, Parma, Italy
Unit of Hematology and Bone Marrow Transplantation, University Hospital of Parma, Parma, Italy
Istituto Zooprofilattico Sperimentale of Lombardia and Emilia Romagna "Bruno Ubertini", Brescia, Italy
Department of Animal Health, Pathology Unit, Faculty of Veterinary Medicine, University of Parma, Parma, Italy
Department of Hematology, Oncology and Molecular Medicine, Italian Institute of Public Health, Rome, Italy
Department of Dermatology, University of Rome "Tor Vergata", Rome, Italy
Department of Internal Medicine, University of Rome "La Sapienza", Parma, Italy
* Corresponding author; email: p.lunghi{at}libero.it.
We here 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 paralogue, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a non functional p53, co-treatment 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 to p53 status, the combined PD/ATO treatment increases the level of the pro-apoptotic protein Bim (PD-mediated) and decreases anti-apoptotic 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 patients outcome in MM.
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