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

Abstract

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.

Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo

“…a potent noncompetitive inhibitor of P-gp [13][14][15] , indicating that there may be a potential pharmacokinetic interaction between Rh2 and the P-gp substrate of PIs. Ritonavir (RTV), one of the most commonly used HIV PIs, has been demonstrated to be a substrate and inhibitor of P-gp both in vitro and in vivo [9,10,16,17] .…”

Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A

“…Although the underlying mechanism of doxorubicin resistance is not fully understood, researchers have determined several factors that influence cellular doxorubicin toxicity. It has been reported that doxorubicin can induce ROS generation in various tumor cells (8,9) and inhibition of P-glycoprotein by 20(S)-Rh2 attenuates adriamycin resistance (10).…”

A Promising Microtubule Inhibitor Deoxypodophyllotoxin Exhibits Better Efficacy to Multidrug-Resistant Breast Cancer than Paclitaxel via Avoiding Efflux Transport

“…MCF-7/A cells have been verified to overexpress P-gp compared to MCF-7/S cells and they exhibit multi-drug resistance (Zhang et al, 2012).…”

“…The efficacy of PTX and DPT on MCF-7/S and Adriamycin-resistant MCF-7/A cells was determined by cell growth inhibition via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2Htetrazolium bromide colorimetric assay after incubation with PTX and DPT under different concentrations. The concentration required to inhibit growth by 50% (IC50 values) were calculated from the survival curves using the Bliss method (Bliss, 1939, Zhang et al, 2012Lu et al, 2015).…”

“…From macrocosm to microcosm, intracellular pharmacokinetics has attracted great attention to the monitoring of intracellular target binding and the intracellular disposition process of drugs (Tulkens, 1990;Krishan et al, 1997), including drug uptake, distribution, metabolism, and efflux within the cellular environment. In recent studies, Adriamycin resistance in MCF-7/A cells was identified by exploring the cellular pharmacokinetic mechanism, which could be reversed by inhibiting P-gp (Zhang et al, 2012). Therefore, intracellular pharmacokinetics has provided a new perspective (Zhou et al, 2011) to determine the underlying mechanisms of MDR, thus promoting efficacy in drug discovery to overcome MDR.…”