α-Lipoic acid prevents against cisplatin cytotoxicity via activation of the NRF2/HO-1 antioxidant pathway

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.

Amelioration of Cisplatin-Induced Ototoxicity in Rats by L-arginine: The Role of Nitric Oxide, Transforming Growth Factor Beta 1 and Nrf2/HO-1 Pathway

“…Recent reports revealed the important role of Nrf2/ HO-1 pathway in the pathophysiology of cisplatininduced cochleotoxicity (Kim et al, 2009). Nrf2 and its downstream enzymes such as HO-1 were proven to protect the cells from oxidative stress induced by cisplatin via regulation of the intracellular redox status (Lee et al, 2019). Nrf2 knockout mice were reported to be more sensitive to the injury induced by ROS in the pulmonary tissues (Vomund et al, 2017).…”

Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

“…For example, dozens of studies show that cisplatin-induced damage to auditory cells is modulated by oxidative stress, inflammation, and autophagy [e.g., (106)(107)(108)(109)(110)(111)]. Several compounds effectively protect HEI-OC1 cells from cisplatin toxicity, including antioxidants such as alpha-lipoic acid and ebselen (106,112,113). Ebselen has now advanced to clinical trials for cisplatin otoprotection, although results are not yet available (clinicaltrials.gov).…”

Protective Effect of Polysaccharides Extracted from Cudrania tricuspidata Fruit against Cisplatin-Induced Cytotoxicity in Macrophages and a Mouse Model

“…Furthermore, the cytoprotective effects of CTPS on nephrotoxicity, which is considered as the most common side effect of cisp treatment, should be investigated using in vitro and in vivo models. In addition, the antioxidant systems, including antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) and their transcription factors (nuclear factor erythroid 2-related factor 2), are closely related to the cytoprotective activity of natural ingredients against chemotherapeutic agents [ 44 , 45 ]. In this regard, to utilize CTPS as a chemotherapeutic supplement, further studies on the role and the underlying mechanism of CTPS activity against other toxic chemotherapeutic agents are needed.…”