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

Abstract

A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V10O28]6– (V10), [H6V14O38(PO4)]5− (V14), [V15O36Cl]6− (V15) and [V18O42I]7− (V18) 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. V10 and V18 were the two most promising compounds, with IC50 values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC50 value of 1.26 µm. V10 and V18 triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V10 with rhodamine B, RhoB-V10. 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.