[Proliferation-inhibiting and multidrug-resistant reversing effect of bortezomib on human HL-60 cells].
OBJECTIVE
To investigate the proliferation-inhibiting and multidrug-resistant reversing effect of bortezomib on human HL-60 cells, and to explore the mechanism of bortezomib-induced proliferation inhibition in human leukemia cells.


METHODS
The multidrug resistant leukemia cell lines HL-60/DNR and HL-60/VCR cells were used as models, and sensitive HL-60 cells as a control. The cytotoxicity of bortezomib on HL-60, HL-60/DNR, HL-60/VCR cells were measured by MTT method, and the non-cytotoxicity dose was determined as reversible dose. The cells were divided into 4 experimental groups: HL-60/DNR + DNR, HL-60/DNR + DNR + bortezomib, HL-60/VCR + VCR, HL-60/VCR + VCR + bortezomib. The bortezomib resistant reversal fold was calculated. The levels of XIAP, cIAP-1, and cIAP-2 mRNA and proteins expression and the activation of NF-κB of the HL-60/DNR, HL-60/VCR cells were examined by quantitative real time RT-PCR and western blot respectively after treated with gradually increasing concentrations of bortezomib (10, 40, 80 nmol/L) for 48 hours.


RESULTS
Bortezomib inhibited the cell growth of HL-60, HL-60/DNR, and HL-60/VCR in a concentration-dependent manner. The IC(50) values were (28.90 ± 3.99), (81.19 ± 9.34), and (73.48 ± 8.94) nmol/L, respectively. After treated with 10nmol/L bortezomib for 48 hours, the IC(50) value of DNR to HL-60/DNR decreased from (12.90 ± 1.75) µmol/L to (3.54 ± 0.57) µmol/L (P < 0.01), and that of VCR to HL-60/VCR from (33.25 ± 7.28) µmol/L to (9.97 ± 1.15) µmol/L (P < 0.01). The reversal fold (RF) values were 3.32 ± 0.53 and 2.64 ± 0.28, respectively. Bortezomib down-regulated the levels of XIAP, cIAP-1, and cIAP-2 mRNA and protein expression and inhibited the NF-κB activation in a concentration-dependent manner.


CONCLUSIONS
Bortezomib can inhibit the proliferation of HL-60 cells and reverse multidrug-resistance in the cells. The possible mechanism is associated with down-regulation of IAPs expression.
Department of Hematology, Fujian Provincial Hospital, Fuzhou, China.
Jin
J
Shang
Zhi-zhong
ZZ
Chen
Wen-bin
WB
Wu
Tian-nan
TN
Wei
Wei-min
WM
Chen
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics
D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib