| Abstract |
Aim: To study the mechanism of multidrug resistance (MDR) of leukemia
cells induced by homoharringtonine (HHT) and the reversal effect of
mifepristone on MDR.
Methods: Human leukemia cell line K562 was induced into MDR cell line by
intermittent administration of high dose of HHT. MTT assay was used to
detect the sensitivity of these MDR cells to all sorts of chemotherapeutic
agents with or without mifepristone. The cytotoxicity of mifepristone was
also observed. RT-PCR was used to detect the expression of MDR1 gene and
glucosylceramide synthase (GCS) gene. Flow cytometry was used to detect
the expression of P-glucoprotein and the accumulative value of
intracellular daunorubicin (DNR) in these MDR cells with or without
mifepristone. Immunohistochemistry was used to detect the expression of
Bcl-2, Bax and caspase-3 in these MDR cells with or without mifepristone.
Results: MDR cell line K562/HHT was acquired after induced by HHT for 2
months. This MDR cell line possessed the ability of 462.6 fold resistance
to HHT and cross-resistance to adriamycin, vincristine and etoposide. The
expression of MDR1 gene, GCS gene, P-glucoprotein and Bcl-2/Bax ratio in
K562/HHT cells were significantly higher than those in K562 cells (P<0.05).
The caspase-3 expression and the accumulative value of intracellular DNR
in K562/HHT cells were significantly lower than those in K562 cells (P<0.05).
10 mum/L mifepristone reversed the resistance of K562/HHT cells to
HHT, adriamycin, vincristine and etoposide at different levels. The
Bcl-2/Bax ratio, caspase-3 expression and accumulative value of intracellular
DNR in K562/HHT cells treated with RU486 were significantly different
compared with K562/HHT cells without RU486 treatment (P<0.05).
Conclusions: Leukemia cell line K562 can be induced into MDR cell line
K562/HHT by HHT. P-glucoprotein, GCS, Bcl-2/Bax ratio and caspase-3 may
play an important role in K562/HHT cells. Mifepristone can reverse MDR in
K562/HHT cells by decreasing the accumulative value of intracellular drug
and regulating the expression of Bcl-2, Bax and caspase-3.
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