Preferential Cochleotoxicity of Cisplatin

Abstract

Cisplatin-induced ototoxicity in humans is more predominant in the cochlea than in the vestibule. Neither definite nor substantial vestibular dysfunction after cisplatin treatment has been consistently reported in the current literature. Inner ear hair cells seem to have intrinsic characteristics that make them susceptible to direct exposure to cisplatin. The existing literature suggests, however, that cisplatin might have different patterns of drug trafficking across the blood-labyrinth-barrier, or different degrees of cisplatin uptake to the hair cells in the cochlear and vestibular compartments. This review proposes an explanation for the preferential cochleotoxicity of cisplatin based on current evidence as well as the anatomy and physiology of the inner ear. The endocochlear potential, generated by the stria vascularis, acting as the driving force for hair cell mechanoelectrical transduction might also augment cisplatin entry into cochlear hair cells. Better understanding of the stria vascularis might shed new light on cochleotoxic mechanisms and inform the development of otoprotective interventions to moderate cisplatin associated ototoxicity.

Keywords: cisplatin; cochlea; cochleotoxicity; ototoxicity; vestibular; vestibulotoxicity.

FIGURE 1

Supporting cells and structures of the inner ear. (A) Schematic drawing of dark cells and transitional cells in the semicircular canal. (B) Schematic drawing of stria vascularis within the cochlea illustrating the marginal, intermediate and basal cell layers. Figures are not drawn to scale.

FIGURE 2

Suggested pathways of cisplatin trafficking in the cochlea. The major entry route for cisplatin entry into the cochlea is via the blood-strial barrier into the stria vascularis, and clearance into the endolymph from the stria vascularis prior to entry into hair cells across their apical membrane. Reproduced with modifications from Kros and Steyger (2018) with permission of Cold Spring Harbor Laboratory Press. OCT2, Organic cation transporter; CTR1, Copper transporter 1; TMC1, Transmembrane channel-like protein 1.