Cisplatin-Induced Ototoxicity: Updates on Molecular Targets

Highlights

• Cisplatin-induced hearing loss may be caused by inflammation, with the initial release of cytokines from existing cellular stocks, followed by the secretion of proinflammatory molecules deriving from de novo synthesis.

• Inflammation and other factors lead to the upregulation of several subunits of NADPH oxidases, altering the balance between free radicals and the antioxidant defense system.

• Reactive oxygen species damage inner ear cell functions through lipid peroxidation, protein nitration, DNA changes, and an amplified inflammatory process.

• Accumulating cell damage in the presence of an overwhelmed defense system leads to cell death, which occurs mainly via intrinsic apoptosis, but also involves autophagy, unfolded protein response, pyroptosis, and necroptosis.

Cis-diamminedichloridoplatinum (II) (cisplatin) is a chemotherapeutic drug currently prescribed for the treatment of many types of human cancer, but its use is associated with numerous adverse effects, one of which is ototoxicity. Cisplatin-induced hearing loss is mainly attributed to oxidative stress, but recent data suggest that inflammation could be the trigger event leading to inner ear cell death through endoplasmic reticulum (ER) stress, autophagy, necroptosis, and then intrinsic apoptosis. In this review, we look at the molecular targets of cisplatin, and the intracellular pathways underlying its ototoxicity. Special attention is devoted to signal transduction processes involving cisplatin that may promote the development of new strategies to prevent cisplatin-induced hearing loss, an adverse event with severe social impacts.