Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures.
CONCLUSIONS
Inhibition of thioredoxin reductase (TrxR) may be a contributing factor in cisplatin-induced ototoxicity. Direct exposure of organ of Corti to cisplatin and oxaliplatin gives equal loss of hair cells.


OBJECTIVE
Platinum-containing drugs are known to target the anti-oxidant selenoprotein TrxR in cancer cells. Two such anti-cancer, platinum-containing drugs, cisplatin and oxaliplatin, have different side effects. Only cisplatin induces hearing loss, i.e. has an ototoxic side effect that is not seen after treatment with oxaliplatin. The objective of this study was to evaluate if TrxR is a target in the cochlea. Loss of outer hair cells was also compared when cisplatin and oxaliplatin were administered directly to the organ of Corti.


METHODS
Organ of Corti cell culture was used for direct exposure to cisplatin and oxaliplatin. Hair cells were evaluated and the level of TrxR was assessed. Immunohistochemical staining for TrxR was performed. An animal model was used to evaluate the effect on TrxR after treatment with cisplatin and oxaliplatin in vivo.


RESULTS
Direct exposure of cochlear organotypic cultures to either cisplatin or oxaliplatin induced comparable levels of outer hair cell loss and inhibition of TrxR, demonstrating that both drugs are similarly ototoxic provided that the cochlea becomes directly exposed.
Division of Biochemistry, Department of Medical Biochemistry and Biophysics.
Pascal
P
Dammeyer
Victoria
V
Hellberg
Inger
I
Wallin
Göran
G
Laurell
Maria
M
Shoshan
Hans
H
Ehrsson
Elias S J
ES
Arnér
Mette
M
Kirkegaard
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000201:enzymology; D009924:Organ Culture Techniques; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D017207:Rats, Sprague-Dawley; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013880:Thioredoxin-Disulfide Reductase; D002945:Cisplatin