Hearing Protection in Cisplatin Chemotherapy

项目摘要/摘要 顺铂是一种有效的抗癌药物，用于~40%的癌症化疗方案 其他含铂类药物。不幸的是，顺铂也会引起多种有害的毒性作用。 例如耳毒性，这导致了大约100-30万新的听力障碍病例 每年仅在美国的癌症患者中。顺铂所致听力损失(CIHL) 与产生活性氧物种(ROS)有关，导致耳蜗损伤，特别是 外毛细胞(OHC)的丧失。在这方面，抗氧化剂作为自由基清除剂发挥作用 建议用于治疗慢性淋巴细胞性白血病)。然而，抗氧化剂会产生许多问题，如 使顺铂失活，保护肿瘤细胞。到目前为止，还没有有效的临床治疗方法。 已获批准。与抗氧化剂不同，和厚朴酚(HNK)是一种多功能分子 既能保护正常细胞免受氧化损伤，又能增强其抗肿瘤作用 顺铂。HNK对CIHL的保护作用在我们最近的出版物中得到了验证。这个 其机制与Sirtuins的激活有关，sirtuins是抗ROS的关键调节因子 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(SIRT1，2)，线粒体(SIRT3-5)，以及 细胞核(SIRT1、2、6、7)，形成ROS解毒的内在网络。 在这项研究中，sirtuin家族在HNK对chil的保护作用中所起的作用将是 进一步调查。第一，HNK对慢性髓细胞白血病的听力保护作用及激活作用 Sirtuins的作用将在接受化疗的荷瘤小鼠模型中得到进一步验证。 其次，胞浆sirtuins(SIRT1)的重要性将在SIRT1缺乏症模型中得到验证。 第三，线粒体sirtuins(SIRT3和SIRT5)的作用及其对 将使用SIRT3基因敲除小鼠和异柠檬酸脱氢酶2基因敲除小鼠来验证彼此 老鼠。将测量听觉脑干反应和失真产物耳声发射 以评估听力功能。将使用X射线荧光显微镜来验证分布 白金在内耳。免疫染色、共聚焦成像和X射线微型计算机 体层摄影术将用于研究OHC丢失等形态变化。A更多 将对CIHL的机制及其保护有全面的了解。 该项目为利用人类NK细胞进行人体试验奠定了基础，具有重要的临床意义。 用于在化疗中保护听力。此外，拟议的研究还将提供见解 对其他类型的听力损伤的听力保护，如噪音引起的，药物- 诱发的和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.