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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Arsenic Trioxide
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Arsenicals / pharmacology*
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Base Sequence
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Binding Sites / genetics
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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HEK293 Cells
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Humans
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I-kappa B Kinase / biosynthesis
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I-kappa B Kinase / metabolism*
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K562 Cells
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Leukemia / drug therapy*
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Leukemia / metabolism
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Molecular Sequence Data
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Oxides / pharmacology*
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Phosphorylases / antagonists & inhibitors*
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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Protein Binding / genetics
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Sequence Analysis, DNA
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Signal Transduction / drug effects
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / biosynthesis
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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Arsenicals
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Oxides
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Phosphorylases
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I-kappa B Kinase
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Arsenic Trioxide