PMID- 18166786
OWN - NLM
STAT- MEDLINE
DCOM- 20080423
LR  - 20151119
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Linking)
VI  - 93
IP  - 1
DP  - 2008 Jan
TI  - The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells 
      and drug resistance associated with the CD34+ immature phenotype.
PG  - 57-66
LID - 10.3324/haematol.11666 [doi]
AB  - 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. DESIGN AND 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.
FAU - Colado, Enrique
AU  - Colado E
AD  - Department of Haematology, Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Alvarez-Fernandez, Stela
AU  - Alvarez-Fernandez S
FAU - Maiso, Patricia
AU  - Maiso P
FAU - Martin-Sanchez, Jesus
AU  - Martin-Sanchez J
FAU - Vidriales, Maria Belen
AU  - Vidriales MB
FAU - Garayoa, Mercedes
AU  - Garayoa M
FAU - Ocio, Enrique M
AU  - Ocio EM
FAU - Montero, Juan Carlos
AU  - Montero JC
FAU - Pandiella, Atanasio
AU  - Pandiella A
FAU - San Miguel, Jesus F
AU  - San Miguel JF
LA  - eng
PT  - Journal Article
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
RN  - 0 (Antigens, CD34)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Pyrazines)
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Aged
MH  - Antigens, CD34/*biosynthesis
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis
MH  - Boronic Acids/*pharmacology
MH  - Bortezomib
MH  - Cell Line, Tumor
MH  - *Drug Resistance, Neoplasm
MH  - *Gene Expression Regulation, Leukemic
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Leukemia, Myeloid, Acute/*drug therapy/metabolism/*pathology
MH  - Middle Aged
MH  - Phenotype
MH  - Protease Inhibitors/*pharmacology
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Pyrazines/*pharmacology
EDAT- 2008/01/02 09:00
MHDA- 2008/04/24 09:00
CRDT- 2008/01/02 09:00
PHST- 2008/01/02 09:00 [pubmed]
PHST- 2008/04/24 09:00 [medline]
PHST- 2008/01/02 09:00 [entrez]
AID - 93/1/57 [pii]
AID - 10.3324/haematol.11666 [doi]
PST - ppublish
SO  - Haematologica. 2008 Jan;93(1):57-66. doi: 10.3324/haematol.11666.