Abstract

The production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity. We examined the preventive effect of α-lipoic acid (LA) on cisplatin-induced toxicity via its antioxidant effects on in vitro and ex vivo culture systems. To elucidate the mechanism of the antioxidant activity of LA, NRF2 was inhibited using NRF2 siRNA, and the change in antioxidant activity of LA was characterized. MTT assays showed that LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells and had a protective effect against cisplatin-induced cytotoxicity. Intracellular ROS production in HEI-OC1 cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS and increased the expression of the antioxidant proteins HO-1 and SOD1. Ex vivo, the organs of Corti of the group pretreated with LA exhibited better preservation than the group that received cisplatin alone. We also confirmed the nuclear translocation of NRF2 after LA administration, and that NRF2 inhibition decreased the antioxidant activity of LA. Together, these results indicate that the antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway.

Highlights

  • IntroductionCisplatin (cis-diamminedichloroplatinum II) is widely used as a chemotherapeutic agent to effectively treat various cancers

  • Cisplatin is widely used as a chemotherapeutic agent to effectively treat various cancers

  • 0.5 mM lipoic acid (LA) concentration was considered safe in HEI-OC1 cells, and was assumed to have a protective effect against cisplatin

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Summary

Introduction

Cisplatin (cis-diamminedichloroplatinum II) is widely used as a chemotherapeutic agent to effectively treat various cancers. Cisplatin therapy is limited by cellular resistance and severe side effects in normal tissues, including nephrotoxicity, neurotoxicity, and cytotoxicity [1, 2]. More than 60% of cisplatin-treated pediatric patients acquired bilateral toxicity in the conventional treatment range during chemotherapy [3]. Even when they grew up, severe hearing loss, in which the patients require a hearing aid or go deaf, was detected in 36% of CNS tumor survivors and 39% of non-CNS tumor survivors. Serious hearing loss in these patients is associated with a reduction in their social attainment [4]. If hearing loss could be prevented in the patients, many of the socioeconomic costs caused by hearing loss could be saved

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