Open AccessReversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy
Author(s) -
Benkafadar Nesrine,
Menardo Julien,
Bourien Jérôme,
Nouvian Régis,
François Florence,
Decaudin Didier,
Maiorano Domenico,
Puel JeanLuc,
Wang Jing
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606230
Subject(s) - ototoxicity , cisplatin , chemotherapy , hair cell , inner ear , hearing loss , medicine , apoptosis , pharmacology , cancer research , oncology , audiology , chemistry , anatomy , biochemistry
Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin‐induced ototoxicity remains unclear, and hearing preservation during cisplatin‐based chemotherapy in patients is lacking. We found activation of the ATM ‐Chk2‐p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin‐induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient‐derived triple‐negative breast cancer protected auditory function, without compromising the anti‐tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin‐based chemotherapy.