Antiestrogenic effect of 20S-protopanaxadiol and its synergy with tamoxifen on breast cancer cells.
BACKGROUND
20S-protopanaxadiol (aPPD) is a major gastrointestinal metabolic product of ginsenosides. The latter share structural similarity with steroids and are the main pharmacologically active component in ginseng.


METHODS
The authors investigated the interaction between aPPD and estrogen receptors (ER) in human breast adenocarcinoma MCF-7 cells through receptor binding assay, ER-induced gene expression, and cell proliferation both in vitro and in vivo.


RESULTS
aPPD, but not its close analog ginsenosides, competed with the [(3)H]-17-beta estradiol (E2) for ER with IC(50) at 26.3 microM. aPPD alone weakly induced luciferase reporter-gene expression controlled by an estrogen-regulated element, which was completely blocked by tamoxifen. aPPD alone, or in synergy with tamoxifen, blocked E2-induced transcriptional activation. aPPD also inhibited colony formation of endometrial cancer cells. aPPD potently inhibited estrogen-stimulated MCF-7 cell proliferation and synergistically enhanced the cytotoxicity of tamoxifen on both ER+ MCF-7 and ER- MDA-MB231 cells. Furthermore, aPPD, but not tamoxifen, inhibited Akt phosphorylation. Growth of MCF-7 xenograft tumor supplemented with E2 was completely inhibited in animals treated with aPPD, tamoxifen, or aPPD plus tamoxifen.


CONCLUSIONS
These results suggested that aPPD inhibits estrogen-stimulated gene expression and cell proliferation in ER-positive breast cancer cells. In addition, aPPD synergistically enhances cytotoxicity of tamoxifen in an ER-independent fashion, probably by down-regulating Akt activity.
Yu
Yan
Y
Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
Zhou
Qun
Q
Hang
Yan
Y
Bu
Xuexian
X
Jia
William
W
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D005894:Panax; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012502:Sapogenins / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D012502:Sapogenins; D014315:Triterpenes; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt; C062916:protopanaxadiol