The Aquaporin-3-Inhibiting Potential of Polyoxotungstates.

Catarina Pimpão,Manuel Aureliano,Nadiia I Gumerova,Maria Manuela Gaspar,Jacinta O Pinho,Inês V Da Silva,Andreia F Mósca,Graça Soveral,Annette Rompel

doi:10.3390/ijms21072467

Abstract

Polyoxometalates (POMs) are of increasing interest due to their proven anticancer activities. Aquaporins (AQPs) were found to be overexpressed in tumors bringing particular attention to their inhibitors as anticancer drugs. Herein, we report for the first time the ability of polyoxotungstates (POTs), such as of Wells–Dawson P2W18, P2W12, and P2W15, and Preyssler P5W30 structures, to affect aquaporin-3 (AQP3) activity and impair melanoma cell migration. The tested POTs were revealed to inhibit AQP3 function with different effects, with P2W18, P2W12, and P5W30 being the most potent (50% inhibitory concentration (IC50) = 0.8, 2.8, and 3.2 µM), and P2W15 being the weakest (IC50 > 100 µM). The selectivity of P2W18 toward AQP3 was confirmed in yeast cells transformed with human aquaglyceroporins. The effect of P2W12 and P2W18 on melanoma cells that highly express AQP3 revealed an impairment of cell migration between 55% and 65% after 24 h, indicating that the anticancer properties of these compounds may in part be due to the blockage of AQP3-mediated permeability. Altogether, our data revealed that P2W18 strongly affects AQP3 activity and cancer cell growth, unveiling its potential as an anticancer drug against tumors where AQP3 is highly expressed.

Highlights

Polyoxometalates (POMs) are discrete metal oxo anions of transition metals such as Mo, W, V, and Nb amenable to a variety of structural transformations
In order to assess the potential inhibitory activity of POTs on AQP3 function, we firstly studied the effects of four solutions of polyoxotungstates (POTs), K6[α-P2W18O62]·14H2O, Na12[α-P2W15O56]·24H2O (P2W15), K12[α-H2P2W12O48]·16H2O (P2W12), and (NH4)14[NaP5W30O110]·31H2O (P5W30), on water (Pf) and glycerol permeability (Pgly) in human red blood cells (hRBCs), cells that largely express AQP1 and AQP3 [32], using stopped-flow spectroscopy
Cells were challenged with a hyperosmotic glycerol solution, inducing a fast cell shrinkage followed by cell reswelling due to water and glycerol influx via AQP3 [33] (Figure 2A)

Summary

Introduction

Polyoxometalates (POMs) are discrete metal oxo anions of transition metals such as Mo, W, V, and Nb amenable to a variety of structural transformations. Other elements (most commonly P, Si, Al, As, Sb, etc.) may be included into these structures, or one of the addenda atoms may even be absent and/or substituted by other metals, such as Co, Ni, or Fe. POMs exhibit outstanding physical, chemical, and biochemical properties that remain to be completely understood and applied. POMs exhibit outstanding physical, chemical, and biochemical properties that remain to be completely understood and applied Due to these properties, POMs are studied in environmental, chemical, and industrial fields, in the areas of catalysis, corrosion prevention, smart glasses, and macromolecular crystallography, as well as in biology, such as for cancer treatment, bacterial infection, and diabetes, among others [1,2,3,4,5,6]. The number of POM studies with anticancer effects is increasing, their mechanisms of action in each type of cancer cell are still far from being understood [3]. As the incidence of cancer is increasing every year all over the world, along with the growing resistance effect and high toxicity of chemotherapeutic agents, some researchers chose POMs as alternative anti-tumor substances with promising results in suppressing tumor growth [3,9,11,12,13]

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Conclusion