title: Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line.
abstract: OBJECTIVE
  The zebrafish lateral line can be used to identify small molecules that protect against cisplatin-induced hair cell death.
  
  
  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.
  
  
  CONCLUSIONS
  The zebrafish lateral line was used to identify 2 small molecules that protected against cisplatin-induced hair cell death.
authors: *VM Bloedel Hearing Research Center, †Department of Biological Structure, and ‡Department of Otolaryngology-HNS, University of Washington; ∥Fred Hutchinson Cancer Research Center; and ¶Seattle Children's Hospital, Seattle, Washington, U.S.A.
authors: Andrew J
authors: AJ
authors: Thomas
authors: Patricia
authors: P
authors: Wu
authors: David W
authors: DW
authors: Raible
authors: Edwin W
authors: EW
authors: Rubel
authors: Julian A
authors: JA
authors: Simon
authors: Henry C
authors: HC
authors: Ou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006198:Hair Cells, Auditory / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D053403:Lateral Line System / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D002945:Cisplatin