Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line

AJ Thomas, P Wu, DW Raible, EW Rubel… - Otology & …, 2015 - journals.lww.com
AJ Thomas, P Wu, DW Raible, EW Rubel, JA Simon, HC Ou
Otology & Neurotology, 2015journals.lww.com
Background Cisplatin is a commonly used chemotherapeutic agent, which causes hearing
loss by damaging hair cells of the inner ear. There are currently no FDA-approved
pharmacologic strategies for preventing this side effect. The zebrafish lateral line has been
used successfully in the past to study hair cell death and protection. Methods In this study,
we used the zebrafish lateral line to screen a library of 10,000 small molecules for protection
against cisplatin-induced hair cell death. Dose-response relationships for identified …
Background
Cisplatin is a commonly used chemotherapeutic agent, which causes hearing loss by damaging hair cells of the inner ear. There are currently no FDA-approved pharmacologic strategies for preventing this side effect. The zebrafish lateral line has been used successfully in the past to study hair cell death and protection.
Methods
In this study, we used the zebrafish lateral line to screen a library of 10,000 small molecules for protection against cisplatin-induced hair cell death. Dose-response relationships for identified protectants were determined by quantifying hair cell protection. The effect of each protectant on uptake of a fluorescent cisplatin analog was also quantified.
Results
From this screen, we identified 2 compounds exhibiting dose-dependent protection: cisplatin hair cell protectant 1 and 2 (CHCP1 and 2). CHCP1 reduced the uptake of a fluorescent cisplatin analog, suggesting its protective effects may be due to decreased cisplatin uptake. CHCP2 did not affect uptake, which suggests an intracellular mechanism of action. Evaluation of analogs of CHCP2 revealed 3 additional compounds that significantly reduced cisplatin-induced hair cell death, although none exceed the effectiveness or potency of the parent compound.
Conclusion
The zebrafish lateral line was used to identify 2 small molecules that protected against cisplatin-induced hair cell death.
Lippincott Williams & Wilkins