PS-341 (Bortezomib) inhibits proliferation and induces apoptosis of megakaryoblastic MO7-e cells.
PS-341 (Bortezomib) is a dipeptide boronic acid proteasome inhibitor with antitumor activity that induces apoptosis in different human cancer cell lines. We investigated effects of PS-341 (Bortezomib) on cell proliferation, cell cycle progression, induction of apoptosis and differentiation in a megakaryoblastic (MO7-e) cell line. PS-341 was able to retain NF-kappaB in the cytoplasm and inhibit cell growth (IC(50)=22.5 nM), in a dose/time-dependent way. This anti-proliferative activity resulted to be lineage-specific, because other leukemic cell lines (KG1a, K562/R7, HL60/DNR) were unaffected by the PS-341 treatment. Moreover, PS-341 in MO7-e induced a significant pro-apoptotic effect from 10 nM concentration (40% versus 12% in the control, p<0.05). On the other hand, at lower concentration (5 nM), Bortezomib blocked cell cycle in the G2 phase. Finally, this compound was able to down-regulate WT1 expression. No significant effects on cell differentiation were found. Because a spontaneous NF-kappaB activation has been reported in megakaryocytes from patients affected by myeloproliferative disorders, Bortezomib would so be an attractive therapeutic tool for these malignancies, including essential thrombocythemia or idiopathic myelofibrosis. Preliminary data show an inhibiting activity of Bortezomib in the megakaryocytic colonies formation. Finally, also down-regulation of the WT1 gene Bortezomib-driven could be relevant, because of the role that this gene would play in the pathogenesis of acute and chronic myeloproliferative disorders.
Galimberti
S
S
Department of Oncology, Transplant and Advances in Medicine, Section of Hematology, University of Pisa, Ospedale S. Chiara, Via Roma, 56, 56100 Pisa, Italy. s.galimberti@med.unipi.it
Canestraro
M
M
Pacini
S
S
Fazzi
R
R
Orciuolo
E
E
Trombi
L
L
Mattii
L
L
Battolla
B
B
Capodanno
A
A
Collecchi
P
P
Veroni
F
F
Simi
P
P
Piaggi
S
S
Casini
A
A
Petrini
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D016162:Genes, Wilms Tumor; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute; D055728:Primary Myelofibrosis / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D011480:Protease Inhibitors; D017346:Protein Serine-Threonine Kinases; D011719:Pyrazines; D000097782:NF-kappaB-Inducing Kinase