Abstract
We recently reported that schisandrin B (Sch B) was a novel P-glycoprotein (P-gp) inhibitor. In this study, we revealed that Sch B was also an effective inhibitor of multidrug resistance-associated protein 1 (MRP1). The activities of Sch B to reverse MRP1-mediated drug resistance was tested using HL60/ADR and HL60/MRP, the human promyelocytic leukemia cell lines with the overexpression of MRP1 but not P-gp. Sch B resumed daunorubicin and carboxyfluorescein diacetate (CFDA, a specific substrate for MRP1) accumulation and retention in HL60/ADR cells in a time and concentration dependent manner. At the equimolar concentration, Sch B demonstrated significantly stronger potency than probenecid, a MRP1 inhibitor. This study, together with the previous findings, demonstrated that Sch B was a dual inhibitor of P-gp and MRP1, a type suggested to be preferable to the use of combination of two specific modulators to prevent drug-drug interaction and cumulative toxicities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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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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Antibiotics, Antineoplastic / metabolism
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Antibiotics, Antineoplastic / pharmacology
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Cyclooctanes / chemistry
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Cyclooctanes / pharmacology
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Daunorubicin / metabolism
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Daunorubicin / pharmacology
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Drug Resistance, Multiple / drug effects
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Drug Resistance, Neoplasm / drug effects
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Flow Cytometry
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Fluoresceins / administration & dosage
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Fluoresceins / metabolism
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Gene Expression Regulation, Neoplastic
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HL-60 Cells
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Humans
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Lignans / chemistry
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Lignans / pharmacology*
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Molecular Structure
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Polycyclic Compounds / chemistry
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Polycyclic Compounds / pharmacology*
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Probenecid / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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Cyclooctanes
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Fluoresceins
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Lignans
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Multidrug Resistance-Associated Proteins
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Polycyclic Compounds
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RNA, Messenger
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carboxyfluoresceindiacetate
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schizandrin B
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Doxorubicin
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Probenecid
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multidrug resistance-associated protein 1
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Daunorubicin