Polyoxovanadates as new P-glycoprotein inhibitors: insights into the mechanism of inhibition.

A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V O ] (V ), [H V O (PO )] (V ), [V O Cl] (V ) and [V O I] (V ) as inhibitors of three major multidrug resistance-linked ABC transporters: P-glycoprotein (P-gp), ABCG2 and MRP1. All of the POVs selectively inhibited P-gp. V and V were the two most promising compounds, with IC values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC value of 1.26 µm. V and V triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V with rhodamine B, RhoB-V . The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand-binding site, opening new possibilities in the development of potent modulators of ABC transporters.