Abstract
Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.
Highlights
Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug
We investigated the effects of Alpha-lipoic acid (ALA) on cisplatin-induced hearing loss in a mouse model and speculated about the underlying mechanism of antiapoptotic pathways activated by ALA to prevent cisplatin-induced ototoxicity in auditory cell lines in vitro
For the control and ALA groups, changes in auditory brainstem response (ABR) threshold were less than 5 dB in the entire frequency range including the click sound, indicating that ALA treatment in normal mice does not affect hearing ability; the cisplatin group showed significant changes in ABR threshold, confirming that cisplatin treatment leads to significant hearing loss (Fig. 1)
Summary
A small platinum-containing molecule, is a widely used, highly effective anticancer drug. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity. ALA has gained considerable attention as a universal antioxidant following discovery of its role, together with its reduced form dihydrolipoic acid as a redox couple, in free radical quenching, metal chelation, and antioxidant recycling[14,15]
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