title: Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy.
abstract: 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.
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Nesrine
authors: N
authors: Benkafadar
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Julien
authors: J
authors: Menardo
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Jérôme
authors: J
authors: Bourien
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Régis
authors: 0000-0002-0901-4666
authors: R
authors: Nouvian
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Florence
authors: F
authors: François
authors: Laboratoire d'Investigation Pré -Clinique/Service d'Hématologie Clinique, Institut Curie, Paris, France.
authors: Didier
authors: D
authors: Decaudin
authors: CNRS - UPR1142, Institut de Génétique Humaine, Montpellier, France.
authors: Domenico
authors: 0000-0003-4229-5903
authors: D
authors: Maiorano
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors: Jean-Luc
authors: JL
authors: Puel
authors: INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France jing.wang@inserm.fr.|Université de Montpellier, Montpellier, France.
authors: Jing
authors: 0000-0002-2670-719X
authors: J
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy; D002945:Cisplatin / Q000009:adverse effects*; D003638:Deafness / Q000139:chemically induced*; D004195:Disease Models, Animal; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D018072:Hair Cells, Auditory, Outer / Q000502:physiology*; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
keywords: DNA damage; chemotherapy; cisplatin ototoxicity; hearing loss; protection