Περίληψη:
In the present study, the ability of the proteasome inhibitor bortezomib
(BZ), an oxidative stress-inducing agent, to sensitize acute myeloid
leukemia (AML) cells to decitabine (Dacogen(R), DAC; a DNA
methyltransferase inhibitor), in terms of cell viability and
differentiation, was investigated. Kasumi-1 AML (M2) cells were treated
with low-dose DAC (10, 50, 100, 200 or 400 nM), with or without BZ (10
nM). Apoptosis and the cell cycle were evaluated after 24 h of treatment
through fluorescence-assisted cell sorting (FACS) with Annexin
V/propidium iodide and DAPI staining, respectively. The expression
levels of CD193, CD11b, CD13, CD14, CD15, CD16 and CD117 surface
differentiation markers were evaluated by FACS after 6 days of
treatment. The results indicated significant alterations in cell death
and cell cycle phases in Kasumi-1 cells following DAC and BZ combination
treatment compared to untreated cells and cells with single treatments.
Low-dose DAC/BZ combinations significantly enhanced apoptosis and
decreased the population of live Kasumi-1 cells, with 100 and 200 nM of
DAC and 10 nM BZ appearing to have the most potent synergistic effect
according to a combination index. Furthermore, cell cycle profiling
revealed that DAC/BZ treatment synergistically led to G0/G1- and
G2/M-phase arrest. By contrast, DAC appeared to promote monocytic and
granulocytic differentiation of Kasumi-1 cells more effectively alone
than in combination with BZ. BZ acted synergistically with low-dose DAC
in vitro, leading to enhanced apoptosis and G0/G1- and G2/M-phase arrest
in AML cells, hence prohibiting either DNA synthesis or mitosis.
Although further in vivo investigation is necessary, these results
provide a strong rationale for the implementation of a combination
treatment with DAC and bortezomib in AML therapy, followed by DAC alone,
which may achieve better clinical responses and possibly partially
overcome the frequently encountered DAC resistance of patients with AML.
Συγγραφείς:
Mpakou, Vassiliki
Spathis, Aris
Bouhla, Anthi
Mpazani,
Efthimia
Papageorgiou, Sotirios
Gkontopoulos, Konstantinos and
Glezou, Eirini
Thomopoulos, Thomas
Foukas, Periklis
Pappa,
Vasiliki
