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) [V₁₀ O₂₈ ]^6- (V₁₀ ), [H₆ V₁₄ O₃₈ (PO₄ )]^5- (V₁₄ ), [V₁₅ O₃₆ Cl]^6- (V₁₅ ) and [V₁₈ O₄₂ I]^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.

Keywords: ABC transporters; P-glycoprotein; cancer; inhibitors; multidrug resistance; polyoxovanadates.