Current Strategies to Combat Cisplatin-Induced Ototoxicity

Abstract

Cisplatin is widely used for the treatment of a number of solid malignant tumors. However, ototoxicity induced by cisplatin is an obstacle to effective treatment of tumors. The basis for this toxicity has not been fully elucidated. It is generally accepted that hearing loss is due to excessive production of reactive oxygen species by cells of the cochlea. In addition, recent data suggest that inflammation may trigger inner ear cell death through endoplasmic reticulum stress, autophagy, and necroptosis, which induce apoptosis. Strategies have been extensively explored by which to prevent, alleviate, and treat cisplatin-induced ototoxicity, which minimize interference with antitumor activity. Of these strategies, none have been approved by the Federal Drug Administration, although several preclinical studies have been promising. This review highlights recent strategies that reduce cisplatin-induced ototoxicity. The focus of this review is to identify candidate agents as novel molecular targets, drug administration routes, delivery systems, and dosage schedules. Animal models of cisplatin ototoxicity are described that have been used to evaluate drug efficacy and side effect prevention. Finally, clinical reports of otoprotection in patients treated with cisplatin are highlighted. For the future, high-quality studies are required to provide reliable data regarding the safety and effectiveness of pharmacological interventions that reduce cisplatin-induced ototoxicity.

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

“…DDP is still used as a mainstay of chemotherapeutic agent in combination with other drugs or radiotherapy for pancreatic cancer therapy [ 41 ]. However, DDP is commonly associated with acquired drug resistance and high toxicity in clinical settings.…”

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

“…Since young children develop hearing loss at lower cumulative dose and early during cisplatin therapy, audiological monitoring is recommended at each cisplatin cycle [176]. The exact mechanism responsible for hearing loss is not fully understood [174,177,178], but data suggest that cisplatin directly stimulates the production of cytokines leading to inflammation, oxidative stress, endoplasmic reticulum stress and, finally, to various forms of cell death [179]. Currently, there is no treatment to reduce cisplatin ototoxicity [174,177,178].…”

Mitophagy Impairment Aggravates Cisplatin-Induced Ototoxicity

“…Inhibition of endoplasmic reticulum stress has been shown to restore mitochondrial function [12]. Though various interventions, including the usage of small molecule compounds and targeted drug delivery systems, have been reported to reduce the ototoxicity of cisplatin, none of them has been granted FDA approval, and hence, further research is essential [13,14]. Here, we demonstrate that promotion of mitophagy can alleviate the cisplatin-induced ototoxicity, potentially enhancing the tolerability and efficacy of cisplatin treatment regimens.…”