Abstract
Xanthohumol (XN) is a well-known prenylated flavonoid found in Humulus lupulus L. It is involved in several pharmacological activities, including the sensitization of doxorubicin-resistant breast cancer (MCF-7/ADR) cells to doxorubicin (DOX) through a reduction in cell viability and stemness. In the present study, we revealed another mechanism to further explain the reverse of the drug resistance of XN. In the MCF-7/ADR cell line, we found that XN inhibited the efflux functions of ATP-binding cassette subfamily B member 1 (ABCB1). We also observed that XN was a substrate of ABCB1 and stimulated its ATPase activity. Moreover, our results revealed that XN showed a synergic effect with the ABCB1 substrate colchicine (COL) in the MCF-7/ADR cell line. Further, we showed that XN bound to the central transmembrane domain (TMD) site, overlapping with the DOX binding site. This mechanism was supported by molecular modeling and simulation data, which revealed that XN bound to the ABCB1 transmembrane domain, where doxorubicin also binds, and its binding affinity was stronger than that of doxorubicin, resulting in less protein and ligand position fluctuation. These results support the XN-induced reversal of drug resistance via the inhibition of ABCB1-mediated transport of doxorubicin, stimulating ABCB1 ATPase activity and acting as a substrate of ABCB1.
Highlights
ATP-binding cassette subfamily B member 1 (ABCB1; known as p-glycoprotein [Pgp]or multidrug resistance protein 1 [MDR1]) belongs to the family of ABC membrane transporters.The most studied biological role of ABCB1 is exporting chemically unrelated substrates; it is usually involved in MDR to cancer chemotherapy, and the modulation of drug pharmacokinetics and interactions [1,2]
Shareaccount some common we investigated could be a substrate of ABCB1, which might for its drug substrates, we investigated resistance reversing effects. whether XN could be a substrate of ABCB1, which might account for its drug resistance reversing effects
We further confirmed that XN inhibited ABCB1 transport functions via evaluation of the efflux of the ABCB1 substrate, Rho123, from MCF-7/ADR cells
Summary
Inhibitors of ABCB1, as well as its non-toxic substrates, might be used to overcome drug screening for natural phytochemicals, which can inhibit ABCB1-mediated transport, and have the resistance and understand the drug intestinal absorption potential application of reversing resistance [3]. As we have reviewed previously, XN has Xanthohumol (XN, Figure 1) is a well-known prenylated flavonoid that exists uniquely in hops multiple health benefits, mainly including metabolic syndrome attenuating effects, hepatic protection (Humulus lupulus L.), and its general dietary source is beer. Recent XN was considered be an inhibitor ofsensitize the breast cancer resistance protein drugs (ABCG2). ABCB1 and ABCG2 play a vital role in MDR and shareaccount some common we investigated could be a substrate of ABCB1, which might for its drug substrates, we investigated resistance reversing effects. Could bind to ABCB1 with the same binding site of DOX
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