Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.
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.
Lunghi
Paolo
P
Department of Clinical Sciences, University of Parma, Italy. p.lunghi@libero.it
Giuliani
Nicola
N
Mazzera
Laura
L
Lombardi
Guerino
G
Ricca
Micaela
M
Corradi
Attilio
A
Cantoni
Anna Maria
AM
Salvatore
Luigi
L
Riccioni
Roberta
R
Costanzo
Antonio
A
Testa
Ugo
U
Levrero
Massimo
M
Rizzoli
Vittorio
V
Bonati
Antonio
A
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
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