Abstract
The pharmacological modulatory effects of 20(S)-ginsenoside Rg3 (20S-Rg3) on multidrug resistant cancer cells are reported in the present study. The effects of 20(S)-Rg3 on the modulation of doxorubicin (DOX) and vincristine (VCR) resistance were examined in the HL60 multidrug resistant subline of human acute myeloid leukemia cells. Results demonstrated that 20S-Rg3 is as effective as verapamil (Vp) for modulating the high degree primary DOX resistance and low degree VCR cross-resistance expressed by the H160 cell line. Furthermore, the present study demonstrates for the first time, using isobologram analysis, that the combination of 20S-Rg3 and Vp enhances the reversal of DOX and VCR resistance in a supra-additive or at least an additive manner. These results indicate that 20S-Rg3 may be used as a Vp synergizer or as a promising alternative to Vp in the chemosensitization of multidrug resistant acute myeloid leukemia, with far fewer side effects.
Highlights
Multidrug resistance (MDR) is a major obstacle to the effectiveness of currently available cytotoxic drugs
Human acute myeloid leukemia HL60 cell lines were purchased from the American Type Culture Collection (Rockville, MD, USA)
A phenylalkylamine calcium channel blocker, is the first reported chemosensitizer that inhibits MDR [14] and the effects of this agent have been demonstrated in a previous clinical study [15]
Summary
Multidrug resistance (MDR) is a major obstacle to the effectiveness of currently available cytotoxic drugs. Various mechanisms of MDR have been reported, the exact mechanisms of resistance remain unclear. The pharmacological mechanism of MDR appears to be a reduced accumulation of intracellular drugs. This is due to enhanced drug efflux by Abbreviations: 20(S)‐Rg3, 20(S)‐ginsenoside Rg3; Vp, verapamil; DOX, doxorubicin; VCR, vincristine; MDR, multidrug resistance; P‐gp, P‐glycoprotein; BrdU, 5‐bromo‐2'‐deoxyuridine energy‐dependent transmembrane transporters, including P‐glycoprotein (P‐gp), MDR protein‐1 and other similar pumps. In the past few decades, a large number of multidrug efflux pump inhibitors have been described and tested (reviewed in 1 and 2). The dose of the efflux pump modulator used in clinical studies has been limited by significant side effects, for example cardiac toxicity
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