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Screening and Validation of Aquaporin Inhibitors for Cancer Therapeutics
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Aquaporins (AQPs) are transmembrane proteins that facilitate the diffusion of water and glycerol across cell membranes, crucial for water and energy homeostasis. These proteins were found overexpressed in different cancer cells and tissues, being involved in tumor formation, cell proliferation and migration, suggesting their great potential as drug targets for cancer treatment. Identification of novel aquaporin modulators to be used in cancer therapeutics is of utmost importance. In this study, the inhibitory effect of polyoxometalates, vanadium, copper, zinc and gold-based compounds was screened by the stopped-flow technique in human red blood cells (RBCs) and then validated in aquaporin-expressing yeast cells. From the set of polyoxometalates, polyoxotungstate-A (POT-A) revealed as the most promising AQP3 inhibitor with an IC50 of (0.71 ± 0.04) μM. Using yeast cells individually expressing human aquaporins, POT-A showed to selectively inhibit AQP3 with 100% inhibition, corroborating the results of RBCs assays. The vanadium compound P103, showed highly inhibition of AQP1 with an IC50 of (9.11 ± 0.03) μM in RBCs. The gold-based compound RBA29 revealed as a promising AQP3 inhibitor with an IC50 of (2.29 ± 0.03) μM in RBCs. Moreover, compounds RBA29, RBA31 and STAM013 showed an inhibitory effect in AQP9-tranformed yeasts, with an IC50 of (6.64 ± 0.09) μM for RBA29. In addition, investigation of the channel residues important for AQP5 permeability revealed a new gating mechanism where His73 located in the selectivity filter interacts with phosphorylated Ser183, conducting to the pore constriction. Furthermore, the activity of aquaporins from diverse organisms was evaluated, wherein aquaporin from tardigrade revealed to be water selective and exhibited higher water permeability than the other aquaporins tested. Overall, these data contribute to the discovery and design of selective inhibitors with potential therapeutic application.
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aquaporins permeability inhibitors cancer