Dibenzocyclooctadiene lignans: a class of novel inhibitors of multidrug resistance-associated protein 1.
We recently reported that dibenzocyclooctadiene lignans were a novel class of P-glycoprotein (P-gp) inhibitors. In this study, we demonstrated that the lignans of this class were also effective inhibitors of multidrug resistance-associated protein 1 (MRP1). The activities of 5 dibenzocyclooctadiene lignans (schisandrin A, schisandrin B, schisantherin A, schisandrol A, and schisandrol B) to reverse MRP1-mediated drug resistance were tested using HL60/Adriamycin (ADR) and HL60/Multidrug resistance-associated protein (MRP), two human promyelocytic leukemia cell lines with overexpression of MRP1 but not P-gp. The five lignans could effectively reverse drug resistance of the two cell lines to vincristine, daunorubicin, and VP-16. This study, together with our previous reports, proves that dibenzocyclooctadiene lignans have multiple activities against cancer multidrug resistance, including inhibition of P-gp and MRP1, and enhancement of apoptosis. Considering that cancer multidrug resistance (MDR) is multifactorial, agents with broad activities are preferable to the use of combination of several specific modulators to prevent drug-drug interaction and cumulative toxicity.
Li
Ling
L
The Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
Pan
Qiangrong
Q
Sun
Meng
M
Lu
Qinghua
Q
Hu
Xun
X
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D034242:Cyclooctanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D034242:Cyclooctanes; D017705:Lignans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C510994:dibenzocyclooctadiene lignan; C421109:multidrug resistance-associated protein 1