Polyoxovanadates as new P-glycoprotein inhibitors: insights into the mechanism of inhibition
FEBS letters(2022)
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-) (V-10), [H6V14O38(PO4)](5-) (V-14), [V15O36Cl](6-) (V-15) and [V18O42I](7-) (V-18) 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-10 and V-18 were the two most promising compounds, with IC50 values of transport inhibition of 25.4 and 22.7 mu m, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC50 value of 1.26 mu m. V-10 and V-18 triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V-10 with rhodamine B, RhoB-V-10. 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.
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Key words
ABC transporters,cancer,inhibitors,multidrug resistance,P-glycoprotein,polyoxovanadates
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