Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia.
Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60-70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 microM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy.
Conticello
Concetta
C
Department of Biomedical Sciences, Hematology Section, University of Catania, Catania, Italy.
Adamo
Luana
L
Vicari
Luisa
L
Giuffrida
Raffaella
R
Iannolo
Gioacchin
G
Anastasi
Gabriele
G
Caruso
Laura
L
Moschetti
Gaetano
G
Cupri
Alessandra
A
Palumbo
Giuseppe Antonio
GA
Gulisano
Massimo
M
De Maria
Ruggero
R
Giustolisi
Rosario
R
Di Raimondo
Francesco
F
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D000069286:Bortezomib; D020169:Caspases