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 apoptosisinducing 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. © 2008 by The American Society of Hematology.

Lunghi, P., Giuliani, N., Mazzera, L., Lombardi, G., Ricca, M., Corradi, A., et al. (2008). Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. BLOOD, 112(6), 2450-2462 [10.1182/blood-2007-10-114348].

Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways

COSTANZO, ANTONIO;
2008-01-01

Abstract

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 apoptosisinducing 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. © 2008 by The American Society of Hematology.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/35 - Malattie Cutanee e Veneree
English
Con Impact Factor ISI
2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; arsenic trioxide; BIM protein; caspase 8; mitogen activated protein kinase; mitogen activated protein kinase kinase; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; protein mcl 1; protein p53; protein p73; tumor necrosis factor related apoptosis inducing ligand receptor; 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; antineoplastic agent; benzamide derivative; diphenylamine; drug derivative; organoarsenic derivative; oxide; protein kinase inhibitor; adult; aged; animal experiment; animal model; animal tissue; apoptosis; article; cancer cell culture; clinical article; controlled study; cytotoxicity; down regulation; enzyme activation; hematopoietic stem cell; human; human cell; in vivo study; mouse; multiple myeloma; myeloma cell; nonhuman; plasmacytoma; priority journal; signal transduction; tumor regression; upregulation; xenograft; animal; cell culture; drug antagonism; drug effect; drug screening; metabolism; mouse mutant; pathology; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenicals; Benzamides; Diphenylamine; Humans; MAP Kinase Signaling System; Mice; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Multiple Myeloma; Oxides; Protein Kinase Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Lunghi, P., Giuliani, N., Mazzera, L., Lombardi, G., Ricca, M., Corradi, A., et al. (2008). Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. BLOOD, 112(6), 2450-2462 [10.1182/blood-2007-10-114348].
Lunghi, P; Giuliani, N; Mazzera, L; Lombardi, G; Ricca, M; Corradi, A; Cantoni, Am; Salvatore, L; Riccioni, R; Costanzo, A; Testa, U; Levrero, M; Rizzoli, V; Bonati, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34312
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