The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype.
BACKGROUND
Proteasome inhibition represents a promising novel anticancer therapy, and bortezomib is a highly selective reversible inhibitor of the proteasome complex. Acute myeloid leukemia (AML) is an immnunophenotypically heterogeneous group of diseases, with CD34(+) cases being associated with drug resistance and poor outcome. We investigated the effects of bortezomib on the growth and survival of AML cells.


METHODS
We studied the in vitro activity and mechanism of action of bortezomib on both cell lines and fresh cells from 28 AML patients including CD34(+) and CD34(-) cases.


RESULTS
Bortezomib showed potent anti-AML activity (IC(50) < 50 nM), which was greater than that of conventional agents (doxorubicin, cytarabine and fludarabine). Moreover, synergistic effects were observed when bortezomib was administered in combination with doxorubicin and cytarabine. Mechanistically, bortezomib induced accumulation of cells in the G(2)/M phase, with up-regulation of p27, together with cell death through an increase in the mitochondrial outer membrane permeability involving caspase-dependent and -independent pathways. The apoptotic activity of bortezomib on fresh CD34(+) blast cells from patients was similar to that observed on CD34(-)blast cells. Importantly, bortezomib was significantly more active than doxorubicin in the immature CD34(+) cells, while there were no differences in its action on CD34(-) cells.


CONCLUSIONS
Bortezomib induces apoptosis in acute myeloid leukemia cells in vitro. Whether this drug might be useful in the treatment of patients with acute myeloid leukemia can be established only in ad hoc clinical trials.
Colado
Enrique
E
Department of Haematology, Hospital Universitario de Salamanca, Salamanca, Spain.
Alvarez-Fernández
Stela
S
Maiso
Patricia
P
Martín-Sánchez
Jesús
J
Vidriales
Maria Belén
MB
Garayoa
Mercedes
M
Ocio
Enrique M
EM
Montero
Juan Carlos
JC
Pandiella
Atanasio
A
San Miguel
Jesús F
JF
D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex