Benkafadar Nesrine, Menardo Julien, Bourien Jérôme, Nouvian Régis, François Florence, Decaudin Didier, Maiorano Domenico, Puel Jean-Luc, Wang Jing
INSERM - UMR 1051, Institut des Neurosciences de Montpellier, Montpellier, France.
Université de Montpellier, Montpellier, France.
EMBO Mol Med. 2017 Jan;9(1):7-26. doi: 10.15252/emmm.201606230.
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.
顺铂是一种广泛使用的化疗药物，尽管它有显著的耳毒性副作用。迄今为止，顺铂诱导耳毒性的机制仍不清楚，且在接受基于顺铂的化疗的患者中缺乏听力保护措施。我们发现ATM-Chk2-p53通路的激活是顺铂耳毒性的主要决定因素。然而，ATM激活对感觉毛细胞具有相反的作用，既促进外毛细胞死亡又促进内毛细胞存活，这阻碍了对顺铂诱导的耳毒性的预防。然而，令人鼓舞的是，p53的基因或药理学消融显著减轻了耳蜗细胞凋亡，从而保护了听力。重要的是，在携带患者来源的三阴性乳腺癌的小鼠中全身给予p53抑制剂可保护听觉功能，而不会损害顺铂的抗肿瘤疗效。总之，这些发现突出了一种在基于顺铂的化疗中保护听力的新颖且有效的策略。
