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1. Pharmazie. 2012 Feb;67(2):187-92.

The proteasome inhibitor bortezomib reverses P-glycoprotein-mediated leukemia
multi-drug resistance through the NF-kappaB pathway.

Wang H, Wang X, Li Y, Liao A, Fu B, Pan H, Liu Z, Yang W.

Department of Hematology, Shengjing Hospital, China Medical University, Shenyang,
Liaoning, China.

Multi-drug resistance (MDR) is one of the obstacles for leukemia therapy, the
major cause is an overexpression of P-glycoprotein (P-gp) leading to increased
drug efflux. We investigated the reversion of multi-drug resistance and the
possible mechanism by which the proteasome inhibitor bortezomib affects the
expression of the multi-drug resistance gene mdrl in the K562/DNR cell line. The
drug resistance of the cells and the cellular toxicity of bortezomib were
confirmed by MTT. Intracellular drug concentrations and cell apoptosis were
detected by flow cytometry. The expression of mdrl mRNA was examined by
fluorescence quantitative PCR. The expression levels of nuclear factor-kappa B
(NF-kappaB), inhibitor of NF-kappaB (IkappaB) and P-gp were detected by western
blotting, and NF-kappaB activity was detected by ELISA. DNR-induced apoptosis
increased in a dose-dependent manner after adding bortezomib. Bortezomib
decreased IkappaB degradation, decreased NF-kappaB and NF-kappaB p65 activity,
reduced P-gp/mdr1 mRNA expression, and increased the intracellular DNR
concentration in K562/DNR cells in vitro. The bortezomib reversed leukemic
multi-drug resistance in a dose-dependent manner as the result of decreasing
IkappaB degradation, thus preventing the translocation of NF-kappaB into the
nucleus and leading the down-regulation of mdr1 and a reduction in P-gp
expression. Therefore, the intracellular drug concentration increased, and then
apoptosis was induced.

PMID: 22512091 [PubMed - in process]