TY - JOUR
T1 - Cisplatin-induced apoptosis in auditory cells
T2 - Role of death receptor and mitochondrial pathways
AU - Devarajan, Prasad
AU - Savoca, Michelle
AU - Castaneda, M. Patricia
AU - Park, Moon Soo
AU - Esteban-Cruciani, Nora
AU - Kalinec, Gilda
AU - Kalinec, Federico
N1 - Funding Information:
This work was supported by NIH RO1 DK53289 (to P.D.) and NIH R03 DK0005335 and the Taper Foundation (to G.K.).
PY - 2002/12
Y1 - 2002/12
N2 - Cisplatin, a commonly used chemotherapeutic agent, has a major limitation due to its ototoxicity. Previous studies have shown that cisplatin induces apoptosis in auditory sensory cells, but the underlying mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a cochlear cell line, in a dose- and duration-dependent manner. Specific caspase assays revealed an early (6 h) but transient increase in caspase 8 activity, and a delayed (12 h) increase in caspase 9 activity. The enhanced caspase 8 activity was preceded by upregulation of p53 expression, and coincided with cleavage of Bid to its truncated form. This was followed temporally by activation and mitochondrial translocation of Bax, induction of mitochondrial permeability transition, release of cytochrome c into the cytosol, activation of caspase 9, and entry into the execution phase of apoptosis. Our results indicate the involvement of both the death receptor mechanisms as well as mitochondrial pathways in cisplatin-induced apoptosis of auditory cells in an in vitro model system.
AB - Cisplatin, a commonly used chemotherapeutic agent, has a major limitation due to its ototoxicity. Previous studies have shown that cisplatin induces apoptosis in auditory sensory cells, but the underlying mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a cochlear cell line, in a dose- and duration-dependent manner. Specific caspase assays revealed an early (6 h) but transient increase in caspase 8 activity, and a delayed (12 h) increase in caspase 9 activity. The enhanced caspase 8 activity was preceded by upregulation of p53 expression, and coincided with cleavage of Bid to its truncated form. This was followed temporally by activation and mitochondrial translocation of Bax, induction of mitochondrial permeability transition, release of cytochrome c into the cytosol, activation of caspase 9, and entry into the execution phase of apoptosis. Our results indicate the involvement of both the death receptor mechanisms as well as mitochondrial pathways in cisplatin-induced apoptosis of auditory cells in an in vitro model system.
KW - Apoptosis
KW - Auditory cell
KW - Cisplatin
KW - Ototoxicity
UR - http://www.scopus.com/inward/record.url?scp=0036888412&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036888412&partnerID=8YFLogxK
U2 - 10.1016/S0378-5955(02)00634-2
DO - 10.1016/S0378-5955(02)00634-2
M3 - Article
C2 - 12433395
AN - SCOPUS:0036888412
SN - 0378-5955
VL - 174
SP - 45
EP - 54
JO - Hearing Research
JF - Hearing Research
IS - 1-2
ER -