Wedelolactone protects against cisplatin-induced nephrotoxicity in mice via inhibition of organic cation transporter 2. (December 2021)

• Record Type: Journal Article
• Authors: Wang, Guangju; Bi, Yajuan; Xiong, Hui; Bo, Tongwei; Han, Lifeng; Zhou, Lijun; Zhang, Chunze; Zhang, Youcai
• Is Part Of: Human & experimental toxicology. Volume 40(2021)Supplement 12
• Page Start: S447
• Page End: S459
• Publication Date: 2021-12
• Subjects: Wedelolactone -- organic cation transporter 2 -- multidrug and toxin extrusion 1 -- cisplatin -- nephrotoxicity; Toxicology -- Periodicals; 615.9
• DOI: 10.1177/09603271211047915
• Languages: English
• ISSNs: 0960-3271

Abstract

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.