Proteasome inhibition specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins.
Proteasome inhibitors are a novel class of compounds that might increase sensitivity to chemotherapy for acute myeloid leukemia (AML). We quantified apoptosis in THP-1 cells incubated with idarubicin (IDA) alone or together with a low concentration of MG132 or bortezomib. The combination of both drugs yielded a percentage of apoptotic cells that was significantly higher than the additive effect of both drugs administered separately (p < 0.01). Isobologram analysis showed that both MG132 and bortezomib interacted synergistically with IDA to induce apoptosis of THP1 cells. Western blot analysis of Bax and Bim show an acumulation of these pro-apoptotic proteins in THP1 treated cells. This increase in Bim preceded the induction of apoptosis and participated in idarubicin-induced apoptosis. Proteasome inhibition also potentiated IDA-induced apoptosis in primary blast cells from 22 AML patients while no such effect was found on normal lymphocytes, PHA-stimulated lymphocytes, normal cord blood CD34+ cells or bone marrow normal myeloid cells. These data show that MG132 and bortezomib specifically sensitize leukemic cells to IDA through an increase in BIM and Bax pro-apoptotic Bcl-2 family proteins.
Pigneux
Arnaud
A
CHU Bordeaux, Hôpital Haut-Lévêque, Service d'Hématologie, Pessac, France. arnaud.pigneux@chu-bordeaux.fr
Mahon
François-Xavier
FX
Moreau-Gaudry
François
F
Uhalde
Maialene
M
de Verneuil
Hubert
H
Lacombe
Francis
F
Reiffers
Josy
J
Milpied
Noel
N
Praloran
Vincent
V
Belloc
Francis
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D018943:Anthracyclines; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids; D007976:Leupeptins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D015255:Idarubicin