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Actinomycin-D (Act-D) is a highly effective chemotherapeutic agent that induces apoptosis in systemic tissues. Act-D combined with other chemotherapeutic agents exhibits ototoxic effects and causes hearing impairment. To investigate the potential toxic effects of Act-D in the inner ear, we treated cochlear organotypic cultures with varying concentrations of Act-D for different durations. For the first time, we found that Act-D specifically induced HC loss and apoptosis in a dose- and time-dependent manner but not neuronal degeneration. Co-treatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK), a pan cysteine protease inhibitor, significantly reduced HC loss and apoptosis induced by Act-D, indicating increased cell survival. Taken together, Act-D exposure has ototoxic effects on the auditory system, while z-VAD-FMK prevents Act-D-induced hair cell damage.

Hearing loss is a common sensory disorder that affects more than 360 million people worldwide, and is primarily caused by the loss of hair cells (HCs). Ototoxic drugs, viral infections, genetic predisposition, aging or noise all damage HCs. 3β-hydroxysteroid-Δ24 reductase (DHCR24), one enzyme in the cholesterol biosynthetic pathway, is involved in inflammation, oxidative stress and neuroprotection. However, researchers have not determined whether DHCR24 is present in the cochlea and the mechanism by which it exerts its regulatory effect on HC loss. In the present study, we analyzed DHCR24 expression in the postnatal day 1 (P1) rat cochlea and found that DHCR24 was localized in HCs of the organ of Corti. Next, exposure to cisplatin caused HC loss in cochlear organotypic cultures. Then, we inhibited DHCR24 expression with U18666A and observed significantly increased cisplatin-induced damage of cochlear HCs. These findings were consistent with the observed increase in DHCR24 expression in response to cisplatin treatment, and U18666A significantly decreased DHCR24 expression. Finally, DHCR24 inhibition increased the levels of reactive oxygen species and cleaved caspase-3 after cisplatin-induced injury. Collectively, DHCR24 may play a significant role in regulating auditory function and potentially represents a new therapeutic target for the treatment of cisplatin-induced ototoxicity.