Impaired Transport Activity of Human Organic Anion Transporters (OATs) and Organic Anion Transporting Polypeptides (OATPs) by Wnt Inhibitors |
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Authors: | Youmna Ali Tahiatul Shams Zhengqi Cheng Yue Li Chelsea Siu-wai Chun Wenying Shu Xiaofeng Bao Ling Zhu Michael Murray Fanfan Zhou |
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Affiliation: | 1. The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health, New South Wales, 2006 Australia;2. Department of Pharmacy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangdong Province, 511400 China;3. School of Pharmacy, Nantong University, Nantong, Jiangsu Province, 226019 China;4. The University of Sydney, Save Sight Institute, Sydney, New South Wales, 2000 Australia;5. The University of Sydney, Discipline of Pharmacology, Faculty of Medicine and Health, New South Wales 2006, Australia |
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Abstract: | The Wnt/β-catenin signaling pathway is dysregulated in diseases and Wnt inhibitors like PRI-724 are in clinical development. This study evaluated the regulatory actions of PRI-724 and other Wnt inhibitors on the transport activity of human renal Organic anion transporters (OATs) and Organic anion transporting polypeptides (OATPs). The substrate uptake by OAT4 and OATP2B1 was markedly decreased by PRI-724 (Vmax/Km: ~26% and ~17% of corresponding control), with less pronounced decreases in OAT1, OAT3 and OAT1A2. PRI-724 decreased the plasma membrane expression of inhibited OATs/OATPs but didn't affect their total cellular expression. Two model Wnt inhibitors - FH535 and 21H7 - were also tested in comparative studies. Like PRI-724, they also strongly decreased the activities and membrane expression of multiple OATs/OATPs. In contrast, FH535 didn't affect the substrate uptake by organic cation transporters. In control studies, the EGFR inhibitor lapatinib did not inhibit the function of some OATs/OATPs. Together these findings suggest that Wnt inhibitors selectively modulate the function of multiple organic anions transporters, so their clinical use may have unanticipated effects on drug entry into cells. These findings are pertinent to current clinical trials that have been designed to understand the safety and efficacy of new Wnt inhibitor drugs. |
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Keywords: | Organic anion transporters Organic anion transporting polypeptides Wnt inhibitors Molecular regulation OAT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0035" }," $$" :[{" #name" :" text" ," _" :" Organic anion transporter OATP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" Organic anion transporting polypeptide OCT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" Organic cation transporter OCTN1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" organic zwitterion/cation transporter-1 ES" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" estrone-3-sulfate FBS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" Fetal Bovine Serum PAH" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" 4-Aminohippuric acid SLCs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" Solute Carrier transporters |
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