Wedelolactone Is An Inhibitor Of Organic Cation Transporter 2 And Protects Against Cisplatin-induced Nephrotoxicity

Cisplatin is the earliest discovered platinum-based chemotherapeutic agent to treat a variety of solid tumors,such as ovarian cancer,prostate cancer,testicular cancer and so on.However,its clinical application is accompanied by severe side effects,such as nephrotoxicity,ototoxicity and nervous system toxicity.Among them,dose-dependent nephrotoxicity is the main factor limiting its clinical application.Currently,there are no effective treatments for cisplatin-induced renal injury.During glomerular filtration and tubular secretion,cisplatin accumulates in the kidney and causes nephrotoxicity.Cisplatin is the substrate of organic cation transporter 2(OCT2)and multidrug and toxin extrusion 1(MATE1),which are mediated by the uptake and efflux of cisplatin.Cimetidine,a typical OCT2 inhibitor,can protect against cisplatin-induced nephrotoxicity by decreasing the accumulation of cisplatin in the kidney.Therefore,OCT2 inhibitors could be drug candidates for preventing or treating cisplatin induced nephrotoxicity.Wedelolactone is a phenylpropanoid compound with various biological activities,such as anti-cancer,anti-inflammatory,antioxidant activity and liver and kidney protection effects.Our preliminary results showed that wedelolactone is an OCT2 inhibitor,but its inhibitory effect on MATE1 and its protective effect on cisplatininduced cytotoxicity and nephrotoxicity are unclear.The present study aimed to clarify the inhibitory effect of wedelolactone on kidney organic cation transporters and determine the protective effect of wedelolactone on cisplatin-induced nephrotoxicity.The results of the uptake assay showed that wedelolactone was a competitive inhibitor of human and mouse OCT2,a noncompetitive inhibitor of MATE1,and a more potent OCT2 inhibitor over MATE1.Cell viability assay showed that wedelolactone could reduce OCT2-mediated cisplatininduced cytotoxicity without altering the anti-tumor activity of cisplatin.In cisplatininduced acute kidney injury mice,wedelolactone could reduce the levels of BUN and CRE and alleviate the pathological changes of kidney tissue.It also showed antiinflammatory and anti-oxidant activities.In addition,wedelolactone could alter cisplatin pharmacokinetics and reduce the accumulation of cisplatin in cells and kidney tissues.Taken together,wedelolactone is an OCT2 inhibitor and can ameliorate cisplatin-induced nephrotoxicity at least partially by reducing the accumulation of cisplatin in renal tubular cells through inhibition of OCT2 uptake activity.