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 (NIX) 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 NIX efflux in MCF-7/MX cells. PPD and Rh2 also increased NIX 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. (c) 2006 Elsevier Inc. All rights reserved.