Overexpression of
breast cancer resistance
protein ABCG2 confers multidrug resistance in
cancer cells. The GF120918-sensitive
drug efflux activity of human wild-type (R482) ABCG2-transfected cells was used for rational screening of inhibitory
flavonoids and establishment of structure-activity relationships.
Flavones were found more efficient than
flavonols,
isoflavones, and
flavanones. Differentially substituted
flavone derivatives indicated positive
OH effects at position 5, in contrast to positions 3 and 7. A methoxy at position 7 was slightly positive in
tectochrysin, whereas a strong positive effect was produced by prenylation at position 6. The potency of
6-prenylchrysin was comparable with that of
GF120918 (IC50 = 0.3 micromol/L). Both
6-prenylchrysin and
tectochrysin seemed specific for ABCG2 because no interaction was detected with either
P-glycoprotein or
MRP1. The ABCG2 resistance profile in vitro is altered by mutation at
amino acid 482. The R482T mutation limited the effect of prenylation on ABCG2 inhibition. Whereas
GF120918 strongly inhibited the
ATPase activity of wild-type ABCG2, neither
6-prenylchrysin nor
tectochrysin altered the activity. In contrast, all three inhibitors stimulated the
ATPase activity of mutant ABCG2.
6-Prenylchrysin at 0.5 micromol/L efficiently sensitized the growth of wild-type ABCG2-transfected cells to
mitoxantrone, whereas higher concentrations were required for the mutant ones. In contrast, 1 micromol/L
tectochrysin was sufficient to fully sensitize mutant ABCG2-transfected cells, whereas higher concentrations were required for the wild-type ones. Both
flavones exhibited a lower intrinsic cytotoxicity than
GF120918 and were apparently not transported by ABCG2.
6-Prenylchrysin and
tectochrysin therefore constitute new and promising inhibitors for the reversal of ABCG2-mediated
drug transport.