title: Metabolites of ginsenosides as novel BCRP inhibitors.
abstract: We have previously shown ginsenosides derived from Panax ginseng exert opposing effects on angiogenesis. Here, we examined protopanaxadiol-containing ginsenosides (Rg3, Rh2, and PPD) and protopanaxatriol-containing ginsenosides (Rg1, Rh1, and PPT) as potential inhibitors of breast cancer resistance protein (BCRP). Among these ginsenosides, metabolites Rh2, PPD, and PPT significantly enhanced the cytotoxicity of mitoxantrone (MX) to human breast carcinoma MCF-7/MX cells which overexpress BCRP. PPD was the most potent followed by Rh2 and PPT. This effect was not seen in sensitive MCF-7 cells. Rg3, Rg1, and Rh1 were ineffective in either MCF-7 or MCF-7/MX cells. PPD, Rh2, and PPT were able to inhibit MX efflux in MCF-7/MX cells. PPD and Rh2 also increased MX uptake. In inside out membrane vesicles from Lactococcus lactis cells expressing BCRP, only PPD was found to significantly inhibit BCRP-associated vanadate sensitive ATPase activity. These results indicate that metabolites PPD, Rh2, and PPT were inhibitors of BCRP.
authors.affiliation: Department of Pharmacology, University of Cambridge, UK. tpf1000@cma.ac.uk
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Sanjay
authors.initials: S
authors.lastname: Shahi
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Kang
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: van Veen
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression; D036145:Ginsenosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D036145:Ginsenosides; D009363:Neoplasm Proteins; D004317:Doxorubicin; D008942:Mitoxantrone; D000251:Adenosine Triphosphatases; C070990:vanadate-sensitive ATPase