Schisandrin B: a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1.
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.
Sun
Meng
M
The Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
Xu
Xiaoli
X
Lu
Qinghua
Q
Pan
Qiangrong
Q
Hu
Xun
X
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D034242:Cyclooctanes / Q000737:chemistry / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D005452:Fluoresceins / Q000008:administration & dosage / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011339:Probenecid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D034242:Cyclooctanes; D003630:Daunorubicin; D004317:Doxorubicin; D005452:Fluoresceins; D017705:Lignans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011083:Polycyclic Compounds; D011339:Probenecid; D012333:RNA, Messenger; C027780:carboxyfluoresceindiacetate; C015499:schizandrin B; C421109:multidrug resistance-associated protein 1