Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway

Abstract

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Fig. 1

Representative AG antibiotics of 4,5-and 4,6-disubstituted subclasses. A, 4,5-Disubstituted AGs (neomycin). B, 4,6-Disubstituted AGs (gentamicin). AG = aminoglycoside.

Fig. 2

Cisplatin activation and DNA damage induction. A, Cisplatin aquation. B, Cisplatin adducts interact with DNA to form intrastrand crosslinks between the bases on the same strand. C, Interstrand crosslinks between the bases on opposing strands.

Fig. 3

The upstream potential targets and blocking agents for aminoglycosides and cisplatin entry into the hair cells. CTR-1 = copper transporter-1; MET = mechanoelectrical transduction; OCT-2 = copper transporter-2; siRNA = small interfering RNA; TMC = transmembrane channel; TRP = transient receptor potential.