title: The proteasome inhibitor bortezomib reverses P-glycoprotein-mediated leukemia multi-drug resistance through the NF-kappaB pathway.
abstract: 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.
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China.
authors.forename: Huihan
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Wang
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.forename: Aijun
authors.initials: A
authors.lastname: Liao
authors.forename: Beibei
authors.initials: B
authors.lastname: Fu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Pan
authors.forename: Zhuogang
authors.initials: Z
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D007202:Indicators and Reagents; D020014:K562 Cells; D016328:NF-kappa B / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics
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; D001897:Boronic Acids; D004396:Coloring Agents; D020672:I-kappa B Proteins; D007202:Indicators and Reagents; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D051996:Transcription Factor RelA; D000069286:Bortezomib; C022616:thiazolyl blue