Hearing Protection in Cisplatin Chemotherapy

项目总结/摘要 顺铂是一种有效的抗肿瘤药物，用于约40%的癌症化疗方案， 其他含铂药物。不幸的是，顺铂也诱导多种不需要的毒性作用 例如耳毒性，这导致约10万至30万新的听力障碍病例 每年仅在美国的癌症患者中。顺铂引起的听力损失（CIHL） 与活性氧（ROS）的产生有关，导致耳蜗损伤，特别是 外毛细胞（OHCs）。在这方面，抗氧化剂作为自由基清除剂 建议用于治疗CIHL）。然而，抗氧化剂会产生很多问题， 使顺铂失活并保护肿瘤细胞。到目前为止，没有有效的临床治疗CIHL 已经被批准了。与抗氧化剂不同，和厚朴酚（HNK）是一种多功能分子 它既能保护正常细胞免受氧化损伤，又能增强 顺铂。HNK对CIHL的保护作用在我们最近的出版物中得到了证实。的 机制与抗ROS的关键调节因子sirtuins的活化有关。 细胞中的系统。sirtuin家族由7个脱乙酰酶成员组成，表达于 不同的细胞内位置，包括细胞质（SIRT 1，2），线粒体（SIRT 3 -5），和 细胞核（SIRT 1，2，6，7），并形成ROS解毒的内在网络。 在本研究中，sirtuin家族在HNK对CIHL的保护作用中的作用将被阐明。 进一步调查。首先，HNK对CIHL的听力保护作用和激活 将在进行化疗的荷瘤小鼠模型中进一步验证sirtuins的活性。 其次，将在SIRT 1缺陷模型中验证胞质sirtuins（SIRT 1）的重要性。 第三，线粒体sirtuins（SIRT 3和SIRT 5）的作用及其对细胞凋亡的潜在补偿。 将使用SIRT 3敲除小鼠和异柠檬酸脱氢酶2敲除小鼠验证彼此 小鼠将测量听性脑干反应和畸变产物耳声发射 评估听力功能。X射线荧光显微镜将用于验证分布 在内耳里发现了铂免疫染色共聚焦成像和X射线显微计算机 断层摄影术将用于研究形态学变化，例如OHC损失。一个更 全面了解CIHL的作用机制及其防护。 该项目为HNK的人体试验奠定了基础，具有重要的临床意义 在化疗中保护听力。此外，拟议的研究还将提供深入了解 保护听力免受其他类型的听力损伤，如噪音引起的，药物， 与年龄相关的听力损失。

Project Summary / Abstract Cisplatin is a potent antitumor drug used in ~40% of cancer chemotherapy regimens together with other platinum-based drugs. Unfortunately, cisplatin also induces multiple unwanted toxic effects such as ototoxicity, which contributes to ~100-300 thousand new hearing impairment cases annually among the cancer patients in the US alone. Cisplatin-induced hearing loss (CIHL) is related to the generation of reactive oxygen species (ROS), causing cochlear damage, particularly the loss of outer hair cells (OHCs). In this regard, antioxidants working as free radical scavengers are proposed for treating CIHL). However, antioxidants generate lots of issues such as deactivating cisplatin and protecting tumor cells. To date, no effective clinical treatment for CIHL has been approved. Different to the antioxidants, honokiol (HNK) is a multifunctional molecule that can both protect normal cells from oxidative damage and potentiate the antitumor effect of cisplatin. The protective effects of HNK against CIHL is verified in our recent publication. The mechanism is associated with the activation of sirtuins, the critical regulators of the anti-ROS system in the cells. The sirtuin family is composed of 7 members of deacetylase, expressing in different intracellular locations including cytoplasm (SIRT1, 2), mitochondria (SIRT3-5), and nucleus (SIRT1, 2, 6, 7) and forming an intrinsic network for ROS detoxification. In this study, the roles of the sirtuin family in the protective effects of HNK against CIHL will be further investigated. First, the hearing protective effects of HNK against CIHL and the activation of sirtuins will be further verified in a tumor bearing mouse model undergoing chemotherapy. Second, the significance of cytosolic sirtuins (SIRT1) will be verified in a SIRT1 deficiency model. Third, the role of mitochondria sirtuins (SIRT3 and SIRT5) and their potential compensation to each other will be verified using SIRT3 knockout mice and isocitrate dehydrogenase 2 knockout mice. Auditory brainstem response and distortion product otoacoustic emission will be measured to assess hearing function. X-ray fluorescence microscopy will be used to verify the distribution of platinum in the inner ear. Immunostaining, confocal imaging, and X-ray micro-computed tomography will be applied for studying morphological changes such as OHC loss. A more comprehensive understanding of the mechanism of the CIHL and its protection will be obtained. This project is of great clinical significance by laying the groundwork for human tests using HNK for hearing protection in chemotherapy. Furthermore, the proposed study will also provide insight into hearing protection against other types of hearing impairment, such as noise-induced, drug- induced and age-related hearing loss.