Caspase inhibitor z-VAD-FMK increases the survival of hair cells after Actinomycin-D-induced damage in vitro

Huimin Chang; Fei Sun; Keyong Tian; Weilong Wang; Ke Zhou; Dingjun Zha; Jianhua Qiu

doi:10.1016/j.neulet.2020.135089

Caspase inhibitor z-VAD-FMK increases the survival of hair cells after Actinomycin-D-induced damage in vitro

Neurosci Lett. 2020 Jul 27:732:135089. doi: 10.1016/j.neulet.2020.135089. Epub 2020 May 25.

Authors

Huimin Chang¹, Fei Sun², Keyong Tian², Weilong Wang³, Ke Zhou⁴, Dingjun Zha⁵, Jianhua Qiu⁶

Affiliations

¹ Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China; Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China.
² Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
³ Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
⁴ Center of Clinical Laboratory Medicine of PLA, Department of Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
⁵ Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China. Electronic address: zhadjun@fmmu.edu.cn.
⁶ Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China. Electronic address: qiujh@fmmu.edu.cn.

PMID: 32464263
DOI: 10.1016/j.neulet.2020.135089

Abstract

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.

Keywords: Actinomycin-D; Apoptosis; Hair cells; Reactive oxygen species; Spiral ganglion neurons.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Chloromethyl Ketones / pharmacology*
Animals
Apoptosis / drug effects
Caspase 3 / metabolism
Caspase Inhibitors
Cell Survival / drug effects
Cochlear Nerve / drug effects
Culture
Cysteine Proteinase Inhibitors / pharmacology
Dactinomycin / toxicity*
Hair Cells, Auditory / drug effects*
Humans
Infant, Newborn
Organ of Corti / drug effects
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Spiral Ganglion / drug effects

Substances

Amino Acid Chloromethyl Ketones
Caspase Inhibitors
Cysteine Proteinase Inhibitors
Reactive Oxygen Species
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
Dactinomycin
Caspase 3