Related Experiment Video
Updated: Jun 11, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase
Ryan M Franke1, Ashley M Kosloske, Cynthia S Lancaster
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Purpose:
This study aimed to test the influence of functional renal organic cation transporters (OCT2 in humans, Oct1 and Oct2 in mice) on biomarkers of cisplatin nephrotoxicity, such as urinary activity of N-acetyl-beta-D-glucosaminidase (NAG).
Experimental Design:
Temporal cisplatin-induced nephrotoxicity was assessed by histopathology and biomarkers. Cisplatin-mediated NAG changes and survival were determined in wild-type and Oct1/2(-/-) mice. Identification of OCT2 inhibitors was done in transfected 293Flp-In cells, and the NCI(60) cell line panel was used to assess contribution of OCT2 to cisplatin uptake in cancer cells.
Results:
Classical biomarkers such as blood urea nitrogen and serum creatinine were not elevated until 72 hours after cisplatin administration and substantial kidney damage had occurred. Oct1/2(-/-) mice had 2.9-fold lower NAG by 4 hours (P < 0.0001) and 2.3-fold increased survival (P = 0.0097). Among 16 agents, cimetidine strongly inhibited uptake of tetraethylammonium bromide (P = 0.0006) and cisplatin (P < 0.0001), but did not have an influence on cisplatin uptake in SK-OV-3 cells, the cancer line with the highest OCT2 mRNA levels. In wild-type mice, cimetidine inhibited cisplatin-induced NAG changes (P = 0.016 versus cisplatin alone) to a degree similar to that seen in Oct1/2(-/-) mice receiving cisplatin (P = 0.91). Cumulative NAG activity of >0.4 absorbance units (AU) was associated with 21-fold increased odds for severe nephrotoxicity (P = 0.0017), which was linked with overall survival (hazard ratio, 8.1; 95% confidence interval, 2.1-31; P = 0.0078).
Conclusions:
Cimetidine is able to inhibit OCT2-mediated uptake of cisplatin in the kidney, and subsequently ameliorate nephrotoxicity likely with minimal effect on uptake in tumor cells.
Insights
Cimetidine reduces cisplatin nephrotoxicity by inhibiting organic cation transporter 2 (OCT2) in kidneys. This improves survival in mice, suggesting a potential therapeutic strategy for cancer patients.
Area of Science:
- Pharmacology
- Nephrology
- Oncology
Background:
- Cisplatin is a widely used chemotherapy agent.
- Nephrotoxicity is a significant dose-limiting side effect of cisplatin.
- Organic cation transporters (OCTs) are implicated in cisplatin transport and toxicity.
Purpose of the Study:
- To investigate the role of renal organic cation transporters (OCT2 in humans, Oct1/2 in mice) in cisplatin nephrotoxicity.
- To assess the impact of inhibiting OCT2 on cisplatin-induced kidney damage and survival.
Main Methods:
- Assessed cisplatin nephrotoxicity using histopathology and biomarkers (e.g., NAG) in wild-type and Oct1/2(-/-) mice.
- Identified OCT2 inhibitors in transfected cells and evaluated cisplatin uptake in cancer cell lines.
- Administered cimetidine to wild-type mice to assess its effect on cisplatin-induced nephrotoxicity.
Main Results:
- Oct1/2(-/-) mice exhibited significantly lower NAG levels and increased survival after cisplatin administration.
- Cimetidine inhibited cisplatin uptake in OCT2-expressing cells and reduced cisplatin-induced NAG changes in wild-type mice.
- Higher cumulative NAG activity correlated with increased odds of severe nephrotoxicity and reduced survival.
Conclusions:
- OCT2 plays a crucial role in mediating cisplatin uptake in the kidney, contributing to nephrotoxicity.
- Cimetidine effectively inhibits OCT2-mediated cisplatin uptake in the kidney, ameliorating nephrotoxicity.
- This suggests that OCT2 inhibition could be a therapeutic strategy to reduce cisplatin-induced kidney damage with minimal impact on tumor cell uptake.
