Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss

Abstract

Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and not interfere with its antitumoral activity. Many therapies have been successful in preclinical work, but only a few have shown any protection in the clinic, and none have been approved by the FDA. This review summarizes the clinical and preclinical studies of the most effective small molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field.

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

“…Pharmacologic blockade of this transporter protects against cisplatin ototoxicity. 21 Mechanotransduction (MET) channels may be involved in the uptake of cisplatin. Inhibition of MET channels protects against cisplatin-induced damage to hair cells in zebrafish, and zebrafish mutants lacking these channels were shown to be resistant to cisplatin-induced cell death.…”

“…Inhibition of MET channels protects against cisplatin-induced damage to hair cells in zebrafish, and zebrafish mutants lacking these channels were shown to be resistant to cisplatin-induced cell death. 21…”

“…The molecular mechanisms that underlie cisplatin ototoxicity are reviewed by Hazlitt et al 21 After transport into the cells of the cochlea, cisplatin undergoes hydrolysis to form aqua cisplatin complexes. These complexes are highly reactive and can damage DNA.…”

D‐methionine improves cisplatin‐induced anorexia and dyspepsia syndrome by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration

“…Furthermore, multiple lines of evidences suggest antioxidants ameliorate cisplatin‐induced side effects (gastrointestinal symptoms such as abdominal discomfort, vomiting, delayed gastric emptying, and gastric distension) and enhanced the antioxidant defense systems . Many previous studies have reported that the mechanisms of D‐methionine protect against cisplatin‐induced toxicities are closely related to its antioxidant effect, protect the endogenous antioxidant system in the body, and reduce oxidative stress . Recent studies in our laboratory indicate that D‐methionine provides protection against cisplatin‐induced intestinal damage through the antioxidative and anti‐inflammatory effects of D‐methionine .…”

“…D‐methionine serves as an antioxidant against cisplatin‐induced ototoxicity by protecting the endogenous antioxidant system in the body and forming inactive complexes with cisplatin . In addition, D‐methionine exhibits a variety of actions, not only providing protection against radiation but also providing cytoprotection, nephroprotection, neuroprotection, and weight loss protection .…”