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.

Keywords: cisplatin; cochlea; hearing loss; inflammation; ototoxicity; oxidative stress.

Figure 1

Overview of the cochlear structure and the site of cisplatin absorption. This illustration depicts the anatomical structure of the cochlea, the organ of hearing located within the inner ear, highlighting the various cell types vulnerable to cisplatin-induced damage. The cochlea consists of three fluid-filled compartments: scala vestibuli and scala tympani, filled with Na⁺-rich perilymph, and scala media, filled with K⁺-rich endolymph. The scala media houses the organ of Corti, which comprises the inner hair cells (responsible for auditory transduction), outer hair cells (critical for cochlear amplification), and surrounding supporting cells. Adjacent to the organ of Corti sits the lateral wall, comprising the stria vascularis (responsible for generating and maintaining the endocochlear potential, the driving force for sensory transduction) and spiral ligament (supporting the stria vascularis and cochlear fluid homeostasis). Spiral ganglion neurons innervate the sensory hair cells and transmit auditory signals to the auditory nuclei in the brainstem. Cisplatin enters the endolymph in the scala media through capillaries in the stria vascularis, and is subsequently absorbed by the sensory hair cells in the organ of Corti (red dashed arrows). This figure was created using BioRender.com (accessed on 16 November 2023).

Figure 2

Proposed mechanism of cisplatin-induced cochlear inflammation. Following its entry into the cochlea and uptake by cells via either simple or facilitated diffusion, cisplatin induces an inflammatory response through various signaling pathways, including TLR4–NF-κB activation, TLR4–NF-κB–NLRP3 inflammasome activation, NOX3–NF-κB activation, NOX3–STAT1 activation, XO–NF-κB/STAT1 activation, reductions in antioxidant enzyme levels, STAT3 inhibition, and mast cell degranulation. The upregulation of pro-inflammatory mediators in the cochlea leads to the infiltration and activation of macrophages. Abbreviations: COX-2, cyclooxygenase 2; CTR1, copper-like transporter-1; CXCL1, chemokine (C-X-C motif) ligand 1; IL-1β, interleukin-1β; IL-18, interleukin-18; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; NOX3, NADPH oxidase 3; OCT2, organic cation transporter-2; ROS, reactive oxygen species; STAT1, signal transducer and activator of transcription-1; STAT3, signal transducer and activator of transcription-3; TNF-α, tumor necrosis factor-alpha; TLR4, Toll-like receptor 4; TMC1, transmembrane channel-like protein 1; XO, xanthine oxidase. This figure was created using BioRender.com (accessed on 16 November 2023).