Abstract
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.
Highlights
Pgp together with several other ABC proteins (e.g., ABCG2, MRP1) possesses a very broad substrate spectrum involving xenobiotics, toxic metabolic side products and numerous chemotherapeutic compounds applied in the treatment of various diseases
We measured the effects of 15 dietary polyphenols on the basal and on the verapamilstimulated ATPase activity of Pgp using membrane samples prepared from NIH 3T3
Due to the high Pgp expression level of the NIH 3T3 MDR1 membrane preparations, a 2- to 3-fold maximal stimulation of the Pgp-specific ATPase activity was observed in the presence of verapamil, a known Pgp substrate
Summary
Pgp together with several other ABC proteins (e.g., ABCG2, MRP1) possesses a very broad substrate spectrum involving xenobiotics, toxic metabolic side products and numerous chemotherapeutic compounds applied in the treatment of various diseases Overexpression of Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) in cancer cells and cancer stem cells often renders the malignant tumors resistant to the different cytotoxic agents used in cancer chemotherapy, leading to the phenomenon of multidrug resistance (MDR) [5,6]. ATP depletion or treatment of cells with certain inhibitors of Pgp, such as cyclosporine A (CsA), tariquidar, valinomycin, etc., make the rest of the cell surface Pgps available for UIC2 binding [14,15]. The increase in UIC2 reactivity seems to correlate with the inhibitory effect of the compounds, serving as a tool for identifying potent Pgp inhibitors [15,16]
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