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Review
. 2018 Jul 12;61(13):5512-5524.
doi: 10.1021/acs.jmedchem.7b01653. Epub 2018 Feb 1.

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

Robert A Hazlitt, Jaeki Min, Jian Zuo
Review

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

Robert A Hazlitt et al. J Med Chem. .

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 do 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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Molecular structures of cisplatin and the clinical candidates discussed.
Figure 2
Figure 2
Examples of (a) transtympanic injection for the local administration of a drug to the inner ear and (b) permeation of a drug across the round-window membrane of the cochlea and into the perilymph to reach the targeted auditory cells.
Figure 3
Figure 3
General mechanistic pathways of cisplatin-induced cytotoxicity in auditory cells and the mechanistic pathways by which the otoprotective clinical candidates combat cisplatin toxicity.
Scheme 1
Scheme 1. Depiction of a Cisplatin Complex with STS As Observed by X-ray Crystallography
Scheme 2
Scheme 2. Molecular Mechanisms by Which NAC Combats Cisplatin Cytotoxicity
(A) Deacetylation of NAC yielding cysteine, an important building block in glutathione synthesis. (B) Complex of NAC with cisplatin at a low pH as a mixture of sulfur-bridged dimers as observed by 15N, 195Pt, 13C, and 1H NMR. (C) Complex of NAC with cisplatin at physiological pH as observed by LC-ESI-MS.
Scheme 3
Scheme 3. Oxidation of d-Methionine and Reduction of the Sulfoxide by MsrA
Scheme 4
Scheme 4. Proposed Mechanism for the Formation of cis-[Pt(Met-S,N)2], 3
Met, methionine. Boxed intermediates have been observed by 15N, 195Pt, 13C, and 1H NMR.
Scheme 5
Scheme 5. Metabolism of Amifostine to WR-1065 and Oxidation of WR-1065 to the Disulfide, WR-33278
Scheme 6
Scheme 6. Proposed Catalytic Cycle of Ebselen as a Glutathione Mimic
Figure 4
Figure 4
Proposed mechanism by which flunarizine combats cisplatin-induced cytotoxicity.
See this image and copyright information in PMC

References

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