Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells.

BACKGROUND AND PURPOSE: Intracellular pharmacokinetics of anticancer drugs in multi-drug resistance (MDR) cancer cells is hugely important in the evaluation and improvement of drug efficacy. By using adriamycin as a probe drug in MDR cancer cells, we developed a cellular pharmacokinetic-pharmacodynamic (PK-PD) model to reveal the correlation between cellular pharmacokinetic properties and drug resistance. In addition, the ability of 20(S)-ginsenoside Rh2 (20(S)-Rh2) to reverse MDR was further investigated. EXPERIMENTAL APPROACH: The cellular pharmacokinetics of adriamycin were analysed visually and quantitatively in human breast cancer cells MCF-7 and in adriamycin-resistant MCF-7 (MCF-7/Adr) cells. Mitochondria membrane potential was assayed to evaluate the apoptotic effect of adriamycin. Subsequently, a PK-PD model was developed via MATLAB. KEY RESULTS: Visual and quantitative data of the dynamic subcellular distribution of adriamycin revealed that it accumulated in cells, especially nuclei, to a lesser and slower extent in MCF-7/Adr than in MCF-7 cells. 20(S)-Rh2 increased the rate and amount of adriamycin entering cellular/subcellular compartments in MCF-7/Adr cells through inhibition of P-glycoprotein (P-gp) activity, in turn augmenting adriamycin-induced apoptosis. The integrated PK-PD model mathematically revealed the pharmacokinetic mechanisms of adriamycin resistance in MCF-7/Adr cells and its reversal by 20(S)-Rh2. CONCLUSIONS AND IMPLICATIONS: P-gp, which is overexpressed and functionally active at cellular/subcellular membranes, influences the cellular pharmacokinetic and pharmacological properties of adriamycin in MCF-7/Adr cells. Inhibition of P-gp activity represents a key mechanism by which 20(S)-Rh2 attenuates adriamycin resistance. Even more importantly, our findings provide a new strategy to explore the in-depth mechanisms of MDR and evaluate the efficacy of MDR modulators.