Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions

Abstract

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40–60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling

“…Excessive levels of ROS can result in cellular oxidative damage through the oxidation of proteins, lipids, and DNA [23]. The development of AKI induced by cisplatin is mainly due to the buildup of ROS and lipid peroxidation products, accompanied by decreased levels of antioxidant molecules such as SOD and GSH [24]. The findings of our research indicate that ZP exhibits protective effects on the kidneys in cases of cisplatin-induced AKI through its enhancement of the antioxidant system.…”

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

“…In this paper, the HDAC1-Sp5-p21 pathway was investigated to understand its involvement in the generation of metastasis-initiating microenvironments of pediatric liver cancers, and if the inhibition of this pathway together with cisplatin is effective in the elimination of cancer cells. Although cisplatin is commonly used for HBL patients, this drug is associated with severe side effects including ototoxicity, neurotoxicity and gastrointestinal and hematologic toxicity [30,31]. Further, some patients with pediatric liver cancers are not adequately treated with cisplatin, which manifests as disease progression, relapse and, at times, tumor-associated mortality.…”

Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof against Cisplatin-Induced Hearing Loss in a Rat Model

“…Due to evolutionary proximity, essential mechanisms of toxic damage affecting auditory function in humans, as well as otoprotection, have been unraveled in rats and other rodents at the cellular and molecular levels [96,97]. However, besides similarities, there are also differences, mostly at the organ and whole organism levels [98], which may limit direct translation to the human clinical setting.…”