Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures

Abstract

ConclusionInhibition 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.ObjectivesPlatinum-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.MethodsOrgan 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.ResultsDirect 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.

Immunohistochemical localization of OCT2 in the cochlea of various species

“…The uptake of cisplatin in the cochlea is obligatory for the ototoxic side effects. Our previous findings based on pharmacokinetic studies suggested that the ototoxic effect of cisplatin is related to the drug concentration in the perilymphatic compartments . The findings in this study give no support that OCT2 is primarily involved in the uptake of cisplatin from the systemic circulation but does not exclude an OCT2‐mediated transport from deeper compartments of the cochlea to the target cells for cisplatin.…”

“…Our previous findings based on pharmacokinetic studies suggested that the ototoxic effect of cisplatin is related to the drug concentration in the perilymphatic compartments. 32,37 The findings in this study give no support that OCT2 is primarily involved in the uptake of cisplatin from the systemic circulation but does not exclude an OCT2mediated transport from deeper compartments of the cochlea to the target cells for cisplatin. The complex processes that take place in cisplatin-induced ototoxicity probably involve several series of events, of which influx of the drug to target cells is the crucial first step.…”

Luteolin Suppresses the Proliferation of Gastric Cancer Cells and Acts in Synergy with Oxaliplatin

“…Common antitumor drugs such as oxaliplatin are reliable for the clinical treatment of gastric cancer. However, long-term use of oxaliplatin can result in nephrotoxicity [20], ototoxicity [21], neurotoxicity [22], and myelosuppression [23]. Moreover, the resistance of tumor cells to oxaliplatin reduces the efficacy of the drug and is a major cause of chemotherapy failure [24].…”

A novel familial 9q31.2q32 microdeletion: Muscle cramping, somnolence, fatigue, sensorineural hearing loss, pubertal delay, and short stature

“…18 Thioredoxin is kept in a reduced state by thioredoxin reductase (TXNRD1, OMIM 601112) and its related isoenzymes. Dammeyer et al 19 found that TXNRD1 was strongly expressed in rat cochlea and that exposure to cisplatin and oxaliplatin significantly reduced TXNRD1 activity. Tadros et al 20 demonstrated that TXNRD1 expression was downregulated in mice cochlea with age-related hearing loss.…”