title: 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: Department of Genetics, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Feng
authors: F
authors: Gao
authors: Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Jia
authors: J
authors: Liu
authors: Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Wan Wei
authors: WW
authors: Dong
authors: Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Wei
authors: W
authors: Wang
authors: Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Ying
authors: Y
authors: Wang
authors: The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Dali
authors: D
authors: Cai
authors: Laboratory Animal Center, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Zhihong
authors: Z
authors: Zheng
authors: Department of Genetics, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
authors: Kailai
authors: K
authors: Sun
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008969:Molecular Sequence Data; D010087:Oxides / Q000494:pharmacology*; D006005:Phosphorylases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D006005:Phosphorylases; D051550:I-kappa B Kinase; D000077237:Arsenic Trioxide