title: Natural lignans from Arctium lappa modulate P-glycoprotein efflux function in multidrug resistant cancer cells.
abstract: Arctium lappa is a well-known traditional medicinal plant in China (TCM) and Europe that has been used for thousands of years to treat arthritis, baldness or cancer. The plant produces lignans as secondary metabolites which have a wide range of bioactivities. Yet, their ability to reverse multidrug resistance (MDR) in cancer cells has not been explored. In this study, we isolated six lignans from A. lappa seeds, namely arctigenin, matairesinol, arctiin, (iso)lappaol A, lappaol C, and lappaol F. The MDR reversal potential of the isolated lignans and the underlying mechanism of action were studied using two MDR cancer cell lines, CaCo2 and CEM/ADR 5000 which overexpress P-gp and other ABC transporters. In two-drug combinations of lignans with the cytotoxic doxorubicin, all lignans exhibited synergistic effects in CaCo2 cells and matairesinol, arctiin, lappaol C and lappaol F display synergistic activity in CEM/ADR 5000 cells. Additionally, in three-drug combinations of lignans with the saponin digitonin and doxorubicin MDR reversal activity was even stronger enhanced. The lignans can increase the retention of the P-gp substrate rhodamine 123 in CEM/ADR 5000 cells, indicating that lignans can inhibit the activity of P-gp. Our study provides a first insight into the potential chemosensitizing activity of a series of natural lignans, which might be candidates for developing novel adjuvant anticancer agents.
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120, Heidelberg, Germany.
authors.forename: Shan
authors.initials: S
authors.lastname: Su
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120, Heidelberg, Germany.
authors.forename: Xinlai
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120, Heidelberg, Germany. Electronic address: wink@uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D031170:Arctium / Q000737:chemistry*; D001572:Benzofurans / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D015394:Molecular Structure; D020112:Rhodamine 123 / Q000494:pharmacology; D012639:Seeds / Q000737:chemistry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001572:Benzofurans; D005663:Furans; D005960:Glucosides; D017705:Lignans; D020112:Rhodamine 123; C068935:matairesinol; C000591899:lappaol F; D004317:Doxorubicin; D015107:4-Butyrolactone; C077992:arctiin; C071942:arctigenin
keywords: Arctium lappa; Cancer cells; Lignans; Multidrug resistance; P-glycoprotein