The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear.
OBJECTIVE
Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg(-1) body weight).


METHODS
Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed.


RESULTS
CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment.


CONCLUSIONS
These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.
García-Berrocal
J R
JR
Servicio de Otorrinolaringología, Hospital Universitario Puerta de Hierro, Madrid, Spain. jrgarciab@yahoo.com
Nevado
J
J
Ramírez-Camacho
R
R
Sanz
R
R
González-García
J A
JA
Sánchez-Rodríguez
C
C
Cantos
B
B
España
P
P
Verdaguer
J M
JM
Trinidad Cabezas
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053148:Caspase 3 / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000187:drug effects / Q000276:immunology
D000970:Antineoplastic Agents; D013482:Superoxide Dismutase; D053148:Caspase 3; D002945:Cisplatin