Journal
HUMAN & EXPERIMENTAL TOXICOLOGY
Volume 40, Issue 12_SUPPL, Pages S447-S459Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/09603271211047915
Keywords
Wedelolactone; organic cation transporter 2; multidrug and toxin extrusion 1; cisplatin; nephrotoxicity
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Funding
- Key R&D Projects in the Tianjin Science and Technology Pillar Program [19YFZCSY00420]
- Project of Innovation Foundation of Tianjin University-Qinghai Nationalities University [2020XGP-0074]
- National Natural Science Foundation of China [81673523]
- Natural Science Foundation of Tianjin City [17JCZDJC33000]
- National Key R&D Program of China [2017YFC1700606, 2017YFC1700604]
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Wedelolactone was identified as a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1, showing selectivity to inhibit OCT2 over MATE1. It alleviated cisplatin-induced cytotoxicity and acute kidney injury, suggesting its potential as a natural therapy for preventing cisplatin-induced nephrotoxicity. Further investigations on drug-drug interactions with WEL and substrates of OCT2 and/or MATE1 are warranted.
The balance of cisplatin uptake and efflux, mediated mainly by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1), respectively, determines the renal accumulation and nephrotoxicity of cisplatin. Using transporter-mediated cellular uptake assay, we identified wedelolactone (WEL), a medicinal plant-derived natural compound, is a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1. Wedelolactone showed a selectivity to inhibit OCT2 rather than MATE1. Cytotoxicity studies revealed that wedelolactone alleviated cisplatin-induced cytotoxicity in OCT2-overexpressing HEK293 cells, whereas it did not alter the cytotoxicity of cisplatin in various cancer cell lines. Additionally, wedelolactone altered cisplatin pharmacokinetics, reduced kidney accumulation of cisplatin, and ameliorated cisplatin-induced acute kidney injury in the Institute of Cancer Research mice. In conclusion, these findings suggest a translational potential of WEL as a natural therapy for preventing cisplatin-induced nephrotoxicity and highlight the need for drug-drug interaction investigations of WEL with other treatments which are substrates of OCT2 and/or MATE1.
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