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DOI: 10.1055/s-2003-38483
© Georg Thieme Verlag Stuttgart · New York
Reversal of P-Glycoprotein-Mediated Multidrug Resistance by Protopanaxatriol Ginsenosides from Korean Red Ginseng
Publikationsverlauf
Received: June 24, 2002
Accepted: November 16, 2002
Publikationsdatum:
04. April 2003 (online)
Abstract
The overexpression of P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP) confers multidrug resistance (MDR) to cancer cells. MDR cells can be sensitized to anticancer drugs when treated concomitantly with an MDR modulator. In this study, we investigated whether or not ginseng saponins could reverse MDR mediated by Pgp or MRP. The chemosensitization and drug accumulation effects of ginseng saponins such as the total saponin, protopanaxadiol ginsenosides (PDG), protopanaxatriol ginsenosides (PTG), ginsenosides-Rb1, -Rb2, -Rc, -Rg1 and -Re were tested on the daunorubicin- and doxorubicin-resistant acute myelogenous leukemia sublines (AML-2/D100 and AML-2/DX100), which overexpress Pgp and MRP, respectively. PTG showed cytotoxicity in both sublines and was able to reverse resistance in the AML-2/D100 subline in a concentration-dependent manner. Conversely, other ginseng saponins at concentrations less than 300 μg/mL showed neither cytotoxicity nor chemosensitizing activity in both resistant sublines. Flow cytometry analysis showed that the effect of PTG (100 μg/mL) on drug accumulation of daunorubicin in the AML-2/D100 subline was 2-fold higher than that observed in the presence of verapamil (5 μg/mL) and 1.5 times less than cyclosporin A (3 μg/mL). The maximum non-cytotoxic concentrations of PTG did not appear to increase the Pgp levels, which is in contrast to verapamil and cyclosporin A. PTG at 200 μg/mL or more completely inhibited the azidopine photolabeling of Pgp. The results suggest that PTG has a chemosensitizing effect on Pgp-mediated MDR cells by increasing the intracellular accumulation of drugs through direct interaction with Pgp at the azidopine site. In addition, PTG may have a beneficial effect on cancer chemotherapy with respect to the possibility of long-term use without the concern of Pgp activation.
Abbreviations
AML:acute myelogenous leukemia
DX:doxorubicin
MDR:multidrug resistance
MRP:multidrug resistance-associated protein
MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
PAGE:polyacrylamide gel electrophoresis
PDG:protopanaxadiol ginsenosides
Pgp:P-glycoprotein
PTG:protopanaxatriol ginsenosides
SDS:sodium dodecyl sulfate
Key words
Multidrug resistance - P-glycoprotein - multidrug resistance-associated protein - ginseng saponins - ginsenosides - drug accumulation
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Cheol-Hee Choi
Department of Pharmacology
College of Medicine
Chosun University
375 Seosuk-dong
Dong-gu
Gwangju 501-759
South Korea
Telefon: +82-62-230-6336
Fax: +82-62-232-4045
eMail: chchoi@mail.chosun.ac.kr