Methoxy Stilbenes as Potent, Specific, Untransported, and Noncytotoxic Inhibitors of Breast Cancer Resistance Protein

Abstract

The ABCG2 multidrug transporter is known to confer cancer cell multidrug resistance by causing the efflux of anticancer drugs; therefore, selective inhibitors have the potential to improve chemotherapeutic treatments. Here, various methoxy derivatives of resveratrol are shown to be potent inhibitors of mitoxantrone efflux by ABCG2: among a series of 11 derivatives, compound 9 (3,5,3',4'-tetramethoxy trans-stilbene) had an IC(50) of 0.16 μM and showed a maximal inhibition of 75%, as measured by flow cytometry. It was not transported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survival experiments. Compound 9 had a very low intrinsic cytotoxicity and was able to chemosensitize the growth of resistant ABCG2-transfected HEK293 cells at submicromolar concentrations. Drug-efflux inhibition was specific for ABCG2 since very low effects were observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, which produced a complete and partly competitive but not ABCG2-specific inhibition, since ABCB1 was even more strongly inhibited. The two inhibitors also displayed different effects on the ABCG2 vanadate-sensitive ATPase activity, suggesting that they either bound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining low concentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude that methoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.

Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position

“…Secondly, the requirement for at least two methoxy groups on the phenyl A-ring (through both electrostatic and steric contributions) while a bicyclic unit occupies the B-ring position to provide maximal inhibition, is in agreement with previous observations showing a positive contribution of methoxy groups to the inhibition potency of flavones,10 rotenoids,11 and trans-stilbenes 14. The contribution of methoxy groups at positions 2′ and 4′ was previously observed in other types of chalcones,18–20,28 whereas the effects produced at positions 3′ and 5′ have been characterized here.…”

“…The quinoxaline-containing chalcones appear not to be transported, as is also observed for other types of chalcones19 as well as for flavones,10 methoxylated trans-stilbenes,14 and chromones 15…”

Jatrophanes from Euphorbia squamosa as Potent Inhibitors of Candida albicans Multidrug Transporters

“…This transporter-dependent cross-resistance suggests that 2 and 6 might be themselves transported. 32 In contrast, compound 4 gave low IC 50 values, not significantly different from that of the control cells; such a lack of cross-resistance, with RI values close to unity, suggested the inability of the inhibitor to be transported. The capacity of the three best inhibitors to sensitize yeast growth to the antifungal activity of FLC is detailed in Table 2.…”

New structure–activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity

“…Derivatives of XR9576/tariquidar16 and GF120918/elacridar17 were also ABCG2-specific, but displayed cytotoxicity and a limited in-vivo bioavailability 18. A flavonoid-binding site was identified for chrysin and other flavones,19–21 while methoxy- trans -stilbenes appeared less toxic 22. Lower-affinity rotenoids,23 acridone derivatives,17 and chromones24 appeared to bind to the same site, as for a number of flavones, and benzo-pyrane/furane derivatives, of which three-dimensional quantitative structure-activity relationship analyses allowed to establish a molecular model 25,26.…”