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) [V 10 O 28 ] 6-(V 10 ), [H 6 V 14 O 38 (PO 4 )] 5− (V 14 ), [V 15 O 36 Cl] 6− (V 15 ) and [V 18 O 42 I] 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 IC 50 values of transport inhibition of 25.4 and 22.7 µM, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC 50 value of 1.26 µM. 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.

Non‐Covalent and Covalent Binding of New Mixed‐Valence Cage‐like Polyoxidovanadate Clusters to Lysozyme

“…It is interesting to note that this is the first time that a protein structure bound to a V 15 cage is reported in the literature, although it has been demonstrated that [V 15 O 36 -(OH 2 )] 5À can inhibit the multidrug resistance-linked ABC transporter P-glycoprotein (P-gp) [5,54] and can act as indirect activator of a G protein-coupled receptor. [55] Here, we show at atomic level that the interaction of the V 15 cage with a protein occurs, possibly influencing the biological activity.…”

In Vitro, Oral Acute, and Repeated 28-Day Oral Dose Toxicity of a Mixed-Valence Polyoxovanadate Cluster

“…Cell responses for all MVPs were greater than those seen for cells treated with the human chorionic gonadotropin (hCG) hormone, which was used in reference [ 9 ]. Despite the promising biological effects described for V 15 , to the best of our knowledge, no evidence of toxicity (in vivo assays) was reported [ 2 , 3 , 29 , 30 , 31 , 32 ].…”

“…Cell responses for all MVPs were greater than those seen for cells treated with the human chorionic gonadotropin (hCG) hormone, which was used in reference [9]. Despite the promising biological effects described for V15, to the best of our knowledge, no evidence of toxicity (in vivo assays) was reported [2,3,[29][30][31][32]. Although several POV compounds have demonstrated favorable biological properties, many aspects of the toxicity remain to be further investigated [33].…”