探讨三氧化二砷调节白血病细胞多药耐药相关蛋白 1 表达降低的机制。

Investigation of the mechanism involved in the As2O3-regulated decrease in MDR1 expression in leukemia cells.

机构信息

Department of Genetics, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.

Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.

出版信息

Oncol Rep. 2014 Feb;31(2):926-32. doi: 10.3892/or.2013.2930. Epub 2013 Dec 16.

DOI:10.3892/or.2013.2930

PMID:24337533

Abstract

Arsenic trioxide (As2O3) inhibits the expression of P-glycoprotein (P-gp) in leukemia cells; however, the mechanism behind this inhibition is unclear. The present study aimed to explore the effect of As2O3 on the expression and regulation of P-gp in leukemia cells, and elucidate the mechanism of the reversal of drug resistance. In the present study, electrophoretic mobility shift assay results indicated that p65 binds to the NF-κB binding site of MDR1, specifically in K562/D cells. Expression of p65 and phosphorylated IκB was reduced, while the expression of IκB was increased in K562/D cells treated with As2O3. The activity of luciferase increased up to 9-fold with 40 ng/ml TNF-α, and it was suppressed by ~25% following treatment with 1 µM As2O3. These findings suggest that As2O3 reverses the P-gp-induced drug resistance of leukemia cells through the NF-κB pathway. As2O3 may inhibit the activity of phosphorylase to inhibit IκB phosphorylation, thereby inhibiting NF-κB activity and MDR1 gene expression, leading to reversal of drug resistance.

摘要

三氧化二砷（As2O3）抑制白血病细胞中 P-糖蛋白（P-gp）的表达；然而，这种抑制的机制尚不清楚。本研究旨在探讨 As2O3 对白血病细胞中 P-gp 表达和调节的影响，并阐明耐药逆转的机制。在本研究中，电泳迁移率变动分析结果表明，p65 与 MDR1 的 NF-κB 结合位点结合，特别是在 K562/D 细胞中。K562/D 细胞用 As2O3 处理后，p65 和磷酸化 IκB 的表达减少，而 IκB 的表达增加。用 40ng/ml TNF-α处理后，荧光素酶的活性增加了 9 倍，用 1μM As2O3 处理后，抑制了约 25%。这些发现表明，As2O3 通过 NF-κB 途径逆转白血病细胞中 P-gp 诱导的耐药性。As2O3 可能通过抑制磷酸化酶的活性来抑制 IκB 的磷酸化，从而抑制 NF-κB 的活性和 MDR1 基因的表达，导致耐药性的逆转。