Original Paper

Apoptosis

, Volume 18, Issue 4, pp 393-408

Profiling drug-induced cell death pathways in the zebrafish lateral line

  • Allison B. CoffinAffiliated withVirginia Merrill Bloedel Hearing Research Center, University of WashingtonDepartment of Otolaryngology–Head and Neck Surgery, University of WashingtonDepartment of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, College of Arts and Sciences, Washington State University Email author 
  • , Kay L. WilliamsonAffiliated withVirginia Merrill Bloedel Hearing Research Center, University of WashingtonDepartment of Otolaryngology–Head and Neck Surgery, University of WashingtonDepartment of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, College of Arts and Sciences, Washington State University
  • , Anna MamiyaAffiliated withDepartment of Speech and Hearing Science, University of Washington
  • , David W. RaibleAffiliated withVirginia Merrill Bloedel Hearing Research Center, University of WashingtonDepartment of Biological Structure, University of Washington
  • , Edwin W. RubelAffiliated withVirginia Merrill Bloedel Hearing Research Center, University of WashingtonDepartment of Otolaryngology–Head and Neck Surgery, University of Washington

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Abstract

Programmed cell death (PCD) is an important process in development and disease, as it allows the body to rid itself of unwanted or damaged cells. However, PCD pathways can also be activated in otherwise healthy cells. One such case occurs in sensory hair cells of the inner ear following exposure to ototoxic drugs, resulting in hearing loss and/or balance disorders. The intracellular pathways that determine if hair cells die or survive following this or other ototoxic challenges are incompletely understood. We use the larval zebrafish lateral line, an external hair cell-bearing sensory system, as a platform for profiling cell death pathways activated in response to ototoxic stimuli. In this report the importance of each pathway was assessed by screening a custom cell death inhibitor library for instances when pathway inhibition protected hair cells from the aminoglycosides neomycin or gentamicin, or the chemotherapy agent cisplatin. This screen revealed that each ototoxin likely activated a distinct subset of possible cell death pathways. For example, the proteasome inhibitor Z-LLF-CHO protected hair cells from either aminoglycoside or from cisplatin, while d-methionine, an antioxidant, protected hair cells from gentamicin or cisplatin but not from neomycin toxicity. The calpain inhibitor leupeptin primarily protected hair cells from neomycin, as did a Bax channel blocker. Neither caspase inhibition nor protein synthesis inhibition altered the progression of hair cell death. Taken together, these results suggest that ototoxin-treated hair cells die via multiple processes that form an interactive network of cell death signaling cascades.

Keywords

Hair cell Ototoxicity Neomycin Gentamicin Cisplatin