title: Overcoming of P-glycoprotein-mediated multidrug resistance in K562/A02 cells using riccardin F and pakyonol, bisbibenzyl derivatives from liverworts.
abstract: Riccardin F and pakyonol, macrocyclic bisbibenzyls from Plagiochasm intermedium, have been confirmed to possess antifungic activities against Candida albicans. Herein, we evaluated their anti-tumor activity in vitro by employing K562 and K562/A02 cells, the well-known adriamycin (ADR)-induced multidrug resistance (MDR) tumor cell lines over-expressing P-glycoprotein (P-gp). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays showed that riccardin F and pakyonol ranging from 0 to 6 μg/mL exhibited no inhibitory effects on the growth of the two cell lines. However, in the presence of 3 μg/mL riccardin F or pakyonol (non-cytotoxic concentration), the IC50 of ADR against K562/A02 cells decreased by 2.51- and 4.78-fold, respectively. Flow cytometry showed that riccardin F and pakyonol significantly enhanced the accumulation of ADR in K562/A02 cells. Furthermore, fluorescence intensity detection revealed that the two natural products remarkably increased the retention of rhodamine-123 in K562/A02 cells rather than in K562 cells, indicating that the major cause for riccardin F and pakyonol to reverse P-gp-mediated MDR in K562/A02 cells is probably due to the constrained transport activity of P-gp. This study explores the potential application of bisbibenzyl type compounds as modulators of P-gp-mediated MDR in tumor cells.
authors.affiliation: Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ji
authors.forename: Yanquiu
authors.initials: Y
authors.lastname: Shi
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004988:Ethers, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D035926:Hepatophyta / Q000737:chemistry*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020014:K562 Cells; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001632:Bibenzyls; D004988:Ethers, Cyclic; C572114:pakyonol; C572113:riccardin F; D020112:Rhodamine 123; D004317:Doxorubicin