Document Detail


Profiling drug-induced cell death pathways in the zebrafish lateral line.
MedLine Citation:
PMID:  23413197     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Allison B Coffin; Kay L Williamson; Anna Mamiya; David W Raible; Edwin W Rubel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Apoptosis : an international journal on programmed cell death     Volume:  18     ISSN:  1573-675X     ISO Abbreviation:  Apoptosis     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-21     Completed Date:  2014-01-24     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  9712129     Medline TA:  Apoptosis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  393-408     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / pharmacology
Calpain / antagonists & inhibitors
Caspase Inhibitors / pharmacology
Cell Death*
Cells, Cultured
Cisplatin / pharmacology
Cross-Linking Reagents / pharmacology
Gentamicins / pharmacology*
Guanidines / pharmacology
Hair Cells, Auditory, Inner / drug effects*,  metabolism*
Lateral Line System / cytology,  drug effects*
Leupeptins / pharmacology
Methionine / pharmacology
Neomycin / pharmacology*
Oligopeptides / pharmacology
Protease Inhibitors / pharmacology
Protein Synthesis Inhibitors / pharmacology
Reactive Oxygen Species / metabolism
Zebrafish
Grant Support
ID/Acronym/Agency:
DC004661/DC/NIDCD NIH HHS; DC005987/DC/NIDCD NIH HHS; DC009931/DC/NIDCD NIH HHS; DC011344/DC/NIDCD NIH HHS; F32 DC009931/DC/NIDCD NIH HHS; P30 DC004661/DC/NIDCD NIH HHS; R01 DC005987/DC/NIDCD NIH HHS; R03 DC011344/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Caspase Inhibitors; 0/Cross-Linking Reagents; 0/Gentamicins; 0/Guanidines; 0/Leupeptins; 0/Oligopeptides; 0/Protease Inhibitors; 0/Protein Synthesis Inhibitors; 0/Reactive Oxygen Species; 1404-04-2/Neomycin; 143839-79-6/N-benzyloxycarbonyl-leucyl-leucyl-phenylalaninal; AE28F7PNPL/Methionine; EC 3.4.22.-/Calpain; J97339NR3V/leupeptin; Q20Q21Q62J/Cisplatin; Y25LQ0H97D/nafamostat
Comments/Corrections

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