Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3).
Multidrug resistance has been a major problem in cancer chemotherapy. In this study, in vitro and in vivo modulations of MDR by ginsenoside Rg(3), a red ginseng saponin, were investigated. In flow cytometric analysis using rhodamine 123 as an artificial substrate, Rg(3) promoted accumulation of rhodamine 123 in drug-resistant KBV20C cells in a dose-dependent manner, but it had no effect on parental KB cells. Additionally Rg(3) inhibited [3H]vinblastine efflux and reversed MDR to doxorubicin, COL, VCR, and VP-16 in KBV20C cells. Reverse transcriptase-polymerase chain reaction and immuno-blot analysis after exposure of KBV20C cells to Rg(3) showed that inhibition of drug efflux by Rg(3) was due to neither repression of MDR1 gene expression nor Pgp level. Photo-affinity labeling study with [3H]azidopine, however, revealed that Rg(3) competed with [3H]azidopine for binding to the Pgp demonstrating that Rg(3) competed with anticancer drug for binding to Pgp thereby blocking drug efflux. Furthermore, Rg(3) increased life span in mice implanted with DOX-resistant murine leukemia P388 cells in vivo and inhibited body weight increase significantly.
Kim
Seung-Whan
SW
College of Pharmacy, SungKyunKwan University, Su-Won 440-746, South Korea.
Kwon
Hyog-young
HY
Chi
Dong-Whan
DW
Shim
Jai-Heon
JH
Park
Jong-Dae
JD
Lee
You-Hui
YH
Pyo
Suhkneung
S
Rhee
Dong-Kwon
DK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology*; D000345:Affinity Labels / Q000378:metabolism; D000818:Animals; D001386:Azides / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D004095:Dihydropyridines / Q000378:metabolism; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005456:Fluorescent Dyes / Q000378:metabolism; D036145:Ginsenosides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007624:KB Cells; D007941:Leukemia P388 / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D020112:Rhodamine 123 / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D036145:Ginsenosides; D014316:Tritium; D020112:Rhodamine 123; C097367:ginsenoside Rg3; D014747:Vinblastine; C041130:azidopine