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

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.

• Authors: Feng Gao, Jia Liu, Wan Wei Dong, Wei Wang, Ying Wang, Dali Cai, Zhihong Zheng, Kailai Sun
• Journal: Oncology reports (Oncol Rep) Vol. 31 Issue 2 Pg. 926-32 (Feb 2014) ISSN: 1791-2431 [Electronic] Greece
• PMID: 24337533 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Arsenicals
• Oxides
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Phosphorylases
• I-kappa B Kinase
• Arsenic Trioxide

Topics

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