Reversal effects of droloxifene on multidrug resistance in adriamycin-resistant K562 cell line.
OBJECTIVE
To study the reversal effects of droloxifene (DRO) on multidrug resistance (MDR) in K562 cell line resistant to adriamycin (ADR).


METHODS
K562 cell line resistant to ADR (K562/A02) and K562 cell line sensitive to ADR (K562) were treated with DRO. Using MTT assay, chemosensitivity to ADR in DRO-treated K562 cell lines was studied. Before and after the treatment with DRO 10 micromol/L, MDR1 and GSTpi gene expression were assayed by reverse transcription-polymerase chain reaction and immunocytochemistry assay. Flow cytometry was used to determine intracellular ADR concentration.


RESULTS
DRO significantly reversed MDR in K562/A02 (P < 0.01). After treatment of DRO 20, 10, and 5 micromol/L, the chemosensitivity to ADR was increased to 14, 13, and 4 folds, respectively. The reversal activity of DRO was similar to that of verapamil (VRP). After treated with DRO 10 micromol/L, both MDR1 and GSTpi mRNA expression began to decline on the 2nd day, and significantly decreased on the 5th day (P<0.01). The changes in P-gp and GSTpi protein expression were similar to that of their mRNA expression. Two hours after treatment of DRO 20, 10, and 5 micromol/L, intracellular ADR concentration in K562/A02 was increased to 2.9, 2.3, and 1.5 folds, respectively. However, DRO did not markedly increase ADR accumulation in K562.


CONCLUSIONS
DRO had strong reversal effect on MDR in K562/A02, which was comparable to that of VRP, but the reversal effect was via different pathways.
Li
J
J
Department of Oncology, Cancer Center, Xin Hua Hospital, Shanghai Second Medical University, Shanghai 200092, China. Ljee@citiz.net
Xu
L Z
LZ
Yao
J J
JJ
Guo
W J
WJ
Xia
P
P
Chen
Y
Y
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000975:Antioxidants; D013629:Tamoxifen; C038345:droloxifene; D004317:Doxorubicin