Reversal effect of nuclear factor-κB protease inhibitor PDTC on multidrug resistance of K562/AO₂ cells and its mechanism.
- Author:
Ting-Ting YANG
1
;
Tian-Yang XUE
;
Wei XU
Author Information
1. Department of Pediatrics, Lianyungang Municipal Frist People Hospital, Lianyungang 222002, Jiangsu Province, China.
- Publication Type:Journal Article
- MeSH:
ATP Binding Cassette Transporter, Sub-Family B;
ATP-Binding Cassette, Sub-Family B, Member 1;
metabolism;
Drug Resistance, Multiple;
drug effects;
Drug Resistance, Neoplasm;
drug effects;
Humans;
K562 Cells;
NF-kappa B;
antagonists & inhibitors;
metabolism;
Protease Inhibitors;
pharmacology;
Pyrrolidines;
pharmacology;
Thiocarbamates;
pharmacology
- From:
Journal of Experimental Hematology
2010;18(4):903-908
- CountryChina
- Language:Chinese
-
Abstract:
This study was purposed to investigate the relationship between activation of nuclear factor-κB (NF-κB) and multidrug resistance in K562/AO₂ cells and its mechanism. Human erythroleukemic cell line K562 and its adriamycin-resistant counterpart K562/AO₂ cells were used in the study. After inhibiting the activation of NF-κB with noncytotoxic concentration of antioxidant pyrrolidine dithiocarbamate (PDTC) in vitro, the multiple of drug resistance of K562/AO₂ cells was assessed by MTT assay. RT-PCR and flow cytometry method were used to detect the relative expression of mdr-1 mRNA and P-gp, respectively. The results showed that (1) multidrug resistance of K562/AO₂ cells to ADM was 59 times higher than that of K562 cells. When being pretreated with 0.2 μmol/L PDTC which is noncytotoxic to cells, the IC₅₀ of ADM in K562/AO₂ cells was sharply decreased with relative reverse efficiency of 93.03%, which was more higher than that of classic modifying agents Verapamil (Ver); (2) NF-κB activity of K562/AO₂ cells was significantly higher than that of K562 cells (p < 0.01). When being treated with PDTC, the activation of NF-κB was sharply decreased in K562/AO₂ cells; with 0.2 μmol/L PDTC for 24 hours it decreased to the lowest, nearly to the K562 cell level (p > 0.05); (3) the relative expression of both mdr-1 mRNA and P-gp in K562/AO₂ cells was more higher; the expressions of mdr-1 mRNA and P-gp both were inhibited in K562/AO₂ cell group treated with PDTC for 48 hours. It is concluded that the PDTC used as an inhibitor of NF-κB activity can partially reverse the multidrug resistance of K562/AO₂ cells, which mechanism can be associated with the down-regulation of mdr-1 mRNA and P-gp.
