Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)
Introduction
Cisplatin has been widely used as an anticancer drug in both adult and pediatric populations against malignant solid tumors. Nephrotoxicity is one of the major dose-limiting side effects of cisplatin that hinders the use of higher doses to maximize the antineoplastic effects (Arany and Safirstein, 2003, Sastry and Kellie, 2005). This underscores the urgent need for understanding the kidney-specific accumulation of cisplatin and development of novel strategies to prevent this serious side effect.
Proximal tubular epithelial cells in the kidney can accumulate cisplatin to a greater degree than other organ tissues. The disproportionate accumulation of cisplatin in kidney tissues, which is about 5 times higher than the serum concentration, highly contributes to cisplatin-induced nephrotoxicity (Kuhlmann et al., 1997, Pabla and Dong, 2008). A desirable approach of renal protection may be to prevent from accumulating toxic concentrations of cisplatin in the kidney while maintaining therapeutic concentrations in the circulation. Recent findings demonstrate that organic cation transporters (OCTs) are critical to the nephrotoxicity of platinum agents. The human OCT2, which is primarily expressed at the basolateral membrane of kidney epithelial cells, is a high capacity transporter for the accumulation of cisplatin from the blood into proximal tubules (Filipski et al., 2008). A non-synonymous single-nucleotide polymorphism (SNP, rs316019) in the OCT2 gene has been associated with reduced nephrotoxicity of cisplatin in patients. Moreover, mice lacking Oct2 have decreased urinary excretion of cisplatin while being protected from its nephrotoxicity (Filipski et al., 2009). In addition, cimetidine, an OCT2 inhibitor, reduces the nephrotoxicity of cisplatin in wild-type mice to a degree similar to that seen in Oct1/2−/− mice receiving cisplatin treatment (Franke et al., 2010). Therefore, reduced function on cisplatin uptake transporters in the kidney may protect from cisplatin-induced nephrotoxicity.
In contrast to the basal uptake transporter OCT2, the excretion transporters, including multidrug and toxin extrusion proteins 1 and 2 (MATE1 and MATE2K in humans, Mate1 in rodents) that are located at the apical membrane of proximal tubular cells (Masuda et al., 2006), are responsible for cisplatin excretion into the urine (Otsuka et al., 2005). A significant rise in the levels of plasma creatinine and blood urea nitrogen (BUN), two biomarkers of renal injury, was observed in cisplatin-treated Mate1 knockout (Mate1−/−) mice in comparison to wild-type mice (Nakamura et al., 2010). Pyrimethamine, a potent MATE inhibitor, also significantly increases the levels of creatinine and BUN in the mice receiving cisplatin treatment (Nakamura et al., 2010). Reduced function on cisplatin excretion transporters in the kidney may thus be causative to cisplatin-induced nephrotoxicity.
The basolateral OCTs work in concert with the apical MATEs to eliminate cationic drugs from the circulation to the urine. Increasing evidence indicates that this cationic transport system is an important mechanistic basis for the occurrence of drug–drug interactions (DDIs) (Ayrton and Morgan, 2008, Hillgren et al., 2013, Matsushima et al., 2009, Nies et al., 2011, Wang et al., 2008b). We hypothesized that the drugs co-administrated with cisplatin that are either OCT or MATE inhibitors or both might have an effect on cisplatin accumulation and toxicity in the kidney. Notably, OCTs and MATEs share a broad spectrum of substrates and inhibitors (Nies et al., 2011, Yonezawa, 2012). The protection on cisplatin-induced nephrotoxicity by an OCT inhibitor may be compromised if it also inhibits MATEs. In contrast, a MATE inhibitor may not necessarily exacerbate cisplatin-induced nephrotoxity if it is also a potent OCT inhibitor. To determine if there is any interaction between a drug and cisplatin in the kidney, the relative inhibitory potency of the drug on cisplatin transporters at both the basolateral and apical membranes has to be assessed.
The introduction of 5-hydroxytryptamine-3 receptor (5-HT3) antagonists has been a significant clinical advance in the prevention and treatment of chemotherapy-induced nausea and vomiting, particularly for patients receiving highly emetogenic cisplatin-based regimens (Hesketh et al., 2003). 5-HT3 receptor antagonists such as ondansetron and tropisetron can interact with OCTs and MATEs (Kido et al., 2011, Tzvetkov et al., 2012, Wittwer et al., 2013). In this study, by investigating ondansetron, we sought to determine whether 5-HT3 receptor antagonists could be a risk factor in cisplatin-induced nephrotoxicity. At first, the inhibitory potencies of ondansetron on OCTs and MATEs were determined in the human embryonic kidney 293 (HEK-293) cells overexpressing these transporters, respectively, which function was determined with metformin, a classical substrate for OCTs and MATEs (Chen et al., 2010, Li et al., 2011, Shu et al., 2007, Shu et al., 2008, Tsuda et al., 2009, Wang et al., 2002). We then investigate the in vivo inhibition by ondansetron by conducting the pharmacokinetics of metformin in wild-type and Mate1−/− mice. Lastly, the renal function was assessed in the mice received cisplatin with and without ondansetron.
Section snippets
Chemicals and reagents
The Flp-In transfection system, Dulbecco's modified Eagle's medium (DMEM), PBS, Lipofectamine 2000, hygromycin, Opti-MEM reduced serum medium, TRIzol, and fetal bovine serum were purchased from Invitrogen. The full length cDNAs of human OCT2 (hOCT2), human MATE1 (hMATE1), mouse Oct2 (mOct2) and mMate1 were obtained from Thermo Scientific Inc. (Waltham, MA). The full length cDNA of hMATE2k was purchased from Origene Inc. (Rockville, MD). The pcDNA5-hOCT2, -hMATE1, mOct2, -mMate1, and -hMATE2k
Ondansetron is a much more potent MATE inhibitor than OCT in vitro
Ondansetron has been previously characterized as an inhibitor towards human OCTs and MATEs in high-throughput screenings against a prescription drug library (Kido et al., 2011, Wittwer et al., 2013). In this study, we firstly sought to validate the interaction of ondansetron with OCT2, MATE1, and MATE2-K, using metformin as the probe substrate towards these transporters (Motohashi and Inui, 2013). As indicated by the mRNA expression levels (Fig. 1A) and the function tests with the substrate
Discussion
This study was designed to investigate whether co-administration of ondansetron increased the possibility of nephrotoxicity during the treatment by cisplatin which is a substrate for cationic drug transporters including OCTs and MATEs. Ondansetron was determined in vitro to be a potent MATE inhibitor and a mild OCT inhibitor. This was then studied in vivo in mice. For the first time, we demonstrated that ondansetron may alter the in vivo disposition of cationic drugs mainly via its inhibition
Conflict of interest statement
The authors declare that they have no financial or personal conflicts of interest that influenced, or could be perceived to have influenced, this work.
Acknowledgments
The present study was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Award R01GM099742 (Y.S.) and by the US Food and Drug Administration (FDA) under Award U01FD004320 (J.E.P., Y.S.). Qing Li and Wei Zhang received research support from the National Natural Science Foundation (NNSF) of China (81001445, Q. L.; 81273595, W. Z.). The content is solely the responsibility of the authors and does not necessarily represent the official
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