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Updated: Mar 20, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Development of Cell-Based High-Throughput Chemical Screens for Protection Against Cisplatin-Induced Ototoxicity
Tal Teitz1, Asli N Goktug2, Taosheng Chen2
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Abstract:
Various compounds have been tested in recent years for protection against cisplatin-induced hearing loss, but no compound has yet been FDA approved for clinical use in patients. Towards this goal, we developed an unbiased, high-throughput, mammalian cochlear cell-based chemical screen that allowed quantification of the protection ability of bioactive compounds and ranked them for future testing ex vivo in cochlear explant cultures and in vivo in animal models. In our primary screens, protection in the HEI-OC1 organ of Corti immortalized cell line was measured by the ability of each compound to inhibit caspase-3/7 activity triggered by cisplatin treatment (50 μM cisplatin for 22 h). A total of 4385 unique bioactive compounds were tested in a single dose of 8 μM and promising compounds were validated by dose response curves covering ten, 1:3 serial diluted concentrations. Primary hits were defined as having more than 60 % inhibition of the caspase-3/7 activity. Toxicity of the top compounds was measured by a CellTiter-Glo (CTG) assay that measured the viability of the cells in the presence of compound alone in similar dose responsive analysis. A combination of the caspase-3/7 inhibition activity assay (as measured by IC50) and the CTG viability assay (as determined by LD50) identified the top protective compounds in the HEI-OC1 cells. In the future, the top hits in our screens will be tested for their protective ability ex vivo in mouse cochlear explants and in vivo in animal models. Our mammalian cochlear cell-based, high-throughput chemical screening assays described here can be further modified and represent an initial successful step towards therapeutic intervention of hearing disorders, an unmet medical need of our society.
Insights
Researchers developed a high-throughput screening method to identify compounds protecting against cisplatin-induced hearing loss. This novel approach successfully identified promising candidates for further testing in preclinical models, addressing a critical unmet medical need.
Area of Science:
- Ototoxicity research
- Drug discovery and development
- Cell biology
Background:
- Cisplatin chemotherapy can cause hearing loss, a significant side effect with no approved preventative treatments.
- Existing research has explored various compounds, but none have reached clinical approval for preventing cisplatin-induced ototoxicity.
- There is a pressing need for effective therapeutic interventions to mitigate hearing damage caused by chemotherapy.
Purpose of the Study:
- To develop and implement an unbiased, high-throughput screening platform for identifying compounds that protect against cisplatin-induced ototoxicity.
- To quantify the protective efficacy of bioactive compounds using a mammalian cochlear cell line.
- To rank identified compounds for subsequent validation in ex vivo and in vivo models.
Main Methods:
- Utilized the HEI-OC1 immortalized cochlear cell line for screening.
- Assessed compound protection by measuring inhibition of cisplatin-induced caspase-3/7 activity.
- Tested 4385 unique compounds at 8 μM, followed by dose-response validation for promising hits.
- Determined compound toxicity using the CellTiter-Glo (CTG) assay to measure cell viability.
Main Results:
- Identified primary hits exhibiting >60% inhibition of caspase-3/7 activity.
- Validated top compounds using dose-response curves to determine IC50 (inhibition) and LD50 (toxicity) values.
- Successfully ranked compounds based on a combination of protective efficacy and safety profiles.
- The screening platform demonstrated its capability to identify potential therapeutic agents for hearing loss.
Conclusions:
- Developed a robust mammalian cochlear cell-based, high-throughput chemical screening assay.
- The screening successfully identified and ranked compounds with protective potential against cisplatin-induced ototoxicity.
- This platform represents a significant advancement towards developing therapies for hearing disorders, an area of unmet medical need.
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