title: Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.
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 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.
authors.affiliation: Department of Clinical Sciences, University of Parma, Italy. p.lunghi@libero.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Lunghi
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzera
authors.forename: Guerino
authors.initials: G
authors.lastname: Lombardi
authors.forename: Micaela
authors.initials: M
authors.lastname: Ricca
authors.forename: Attilio
authors.initials: A
authors.lastname: Corradi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cantoni
authors.forename: Luigi
authors.initials: L
authors.lastname: Salvatore
authors.forename: Roberta
authors.initials: R
authors.lastname: Riccioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rizzoli
authors.forename: Antonio
authors.initials: A
authors.lastname: Bonati
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001152:Arsenicals; D001549:Benzamides; D010087:Oxides; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000077237:Arsenic Trioxide