Reversal of P-Glycoprotein-Mediated Multidrug Resistance by Protopanaxatriol Ginsenosides from Korean Red Ginseng

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-Rb 1, -Rb 2, -Rc, -Rg 1 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 microg/mL showed neither cytotoxicity nor chemosensitizing activity in both resistant sublines. Flow cytometry analysis showed that the effect of PTG (100 microg/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 microg/mL) and 1.5 times less than cyclosporin A (3 microg/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 microg/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.

Effects of 19 Herbal Extracts on the Sensitivity to Paclitaxel or 5-Fluorouracil in HeLa Cells

“…Glycyrrhizae Radix, at a low concentration of 1 mg/ml, decreased the sensitivity to paclitaxel and Rhodamine123 uptake, presumably by the acceleration of MDR1 function by Glycyrrhizae Radix. 17) The present findings suggest the existence of a modifying action of some herbal extracts on MDR1, and imply the possibility of reversing MDR1-mediated resistance. The detailed investigations using MDR1-overexpressing HeLa cells are ongoing in our laboratory, but the data have not been obtained yet.…”

Korean Ginseng Berry Fermented by Mycotoxin Non-producing <i>Aspergillus niger</i> and <i>Aspergillus oryzae</i>: Ginsenoside Analyses and Anti-proliferative Activities

“…41) The PPT type ginsenosides have been documented to suppress glycoprotein dependent multidrug resistance and increase the sensitivity of cancer cells to anti-cancer drugs. 42) In addition, PPT type ginsenoside metabolites have been shown to increase the effects of anticancer drug by inhibiting breast cancer resistance protein. 43) Fermentation by A. niger and A. oryzae dramatically increased cytotoxicity of KGB on the HT-29 and HepG2 cell lines, which in turn confirmed that ginsenosides in KGB were highly transformed.…”

Targeting Effect of Traditional Chinese Medicine

“…For example, ginseng is drug usually used to invigorate vital energy, the main components of it not only affected drug metabolism but inhibited P-gp as well (C.H. Choi et al, 2003;S.W. Kim et al, 2003;S.…”