Pifithrin-alpha suppresses p53 and protects cochlear and vestibular hair cells from cisplatin-induced apoptosis.
Cisplatin, a commonly used antineoplastic agent, destroys the sensory hair cells in the cochlear and vestibular system leading to irreversible hearing loss and balance problems. Cisplatin-induced hair cell damage presumably occurs by apoptosis. Recent studies suggest that p53 may play an important role initiating cisplatin-induced apoptosis in some cell types. To determine if p53 plays a role in cisplatin-mediated hair cell loss, cochlear and utricular organotypic cultures were prepared from postnatal day 3-4 rats and treated with cisplatin or cisplatin plus pifithrin-alpha (PFT), a p53 inhibitor. Control cultures were devoid of p53 immunolabeling, caspase-1 and caspase-3 labeling and p53 protein was absent from Western blots. Cisplatin (1-10 microg/ml) caused a dose-dependent loss of hair cells in cochlear and utricular cultures, up-regulated phospho-p53 serine 15 immunolabeling, increased the expression of phospho-p53 serine 15 in Western blots from 6 to 48 h after the onset of cisplatin-treatment, and increased caspase-1 and caspase-3 labeling in cochlear and vestibular cultures. Addition of PFT (20-100 microM) to cisplatin-treated cochlear and utricular cultures resulted in a dose-dependent increase in hair cell survival; suppressed the expression of p53 in Western blots and eliminated caspase-1 and caspase-3 labeling in cultures. These results suggest that the tumor suppressor protein, p53, plays a critical role in initiating apoptosis in cochlear and vestibular hair cells. Temporary suppression of p53 with PFT provides significant protection against cisplatin-induced hair cell loss and offers the potential for reducing the ototoxic, vestibulotoxic and neurotoxic side effects of cisplatin.
Zhang
M
M
Center for Hearing and Deafness, Hearing Research Laboratory, 215 Parker Hall, University at Buffalo, Buffalo, NY 14214, USA.
Liu
W
W
Ding
D
D
Salvi
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D052160:Benzothiazoles; D002945:Cisplatin / Q000633:toxicity; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D051381:Rats; D011916:Rats, Inbred F344; D013844:Thiazoles / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D002945:Cisplatin