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Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective

Giuliano Ciarimboli1, Dirk Deuster, Arne Knief

  • 1Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Domagkstr. 3a, 48149 Münster, Germany. gciari@uni-muenster.de

The American Journal of Pathology
|January 30, 2010
PubMed

Insights

Cisplatin chemotherapy causes severe hearing and kidney damage, but blocking organic cation transporters (OCTs) significantly reduces these toxicities. This discovery offers a way to improve cancer treatment safety, especially for children.

Area of Science:

  • Pharmacology
  • Toxicology
  • Oncology

Background:

  • Cisplatin is an effective chemotherapy drug but causes severe ototoxicity and nephrotoxicity.
  • Ototoxicity is particularly concerning in children, impacting development.
  • Organic cation transporters (OCTs) are known cellular uptake mechanisms for cisplatin.

Purpose of the Study:

  • To investigate the role of OCTs in cisplatin-induced ototoxicity and nephrotoxicity in vivo.
  • To explore potential therapeutic strategies to mitigate cisplatin's side effects.

Main Methods:

  • Studied cisplatin's effects on kidney function and hearing in wild-type and OCT1/2 double-knockout mice.
  • Assessed kidney function via 24-hour excretion of glucose, water, and protein.
  • Evaluated hearing using auditory brainstem response.
  • Investigated OCT expression in cochlear hair cells and pediatric tumor cell lines.

Main Results:

  • Cisplatin-treated knockout mice showed no ototoxicity and only mild nephrotoxicity.
  • Cimetidine co-administration protected wild-type mice from ototoxicity and partly from nephrotoxicity.
  • OCT2 was found to be expressed in cochlear hair cells.
  • Pediatric tumor cell lines showed no OCT mRNA expression.

Conclusions:

  • OCTs, particularly OCT2, play a significant role in cisplatin's toxic effects on hearing and kidneys.
  • Targeting OCT2-mediated cisplatin uptake presents a viable strategy to reduce chemotherapy-related toxicities.
  • This research supports the development of safer cisplatin-based chemotherapeutic protocols.

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