Hearing Protection in Cisplatin Chemotherapy

顺铂化疗中的听力保护

• 批准号: 10548860
• 负责人: Xiaodong Tan
• 金额: $ 40万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548860
• 关键词: Address; Adverse effects; Affect; Aftercare; Animals; Antioxidants; Apoptosis; Auditory Brainstem Responses; Blood; Cancer Patient; Cell Nucleus; Cell physiology; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinic; Clinical; Clinical Treatment; Clinical Trials; Cochlea; Compensation; Cytoplasm; Data; Deacetylase; Dose; Drug Metabolic Detoxication; Drug Screening; Drug Targeting; Drug usage; Elements; Enzymes; Experimental Designs; FDA approved; Family; Fluorescence Microscopy; Free Radical Scavengers; Generations; Hearing; Hearing Protection; Hearing Tests; Human; Inflammation; Isocitrate Dehydrogenase; Knock-out; Knockout Mice; Labyrinth; Location; Longevity; Mammary Neoplasms; Measurement; Measures; Mitochondria; Modeling; Morphology; Mus; Noise; Normal Cell; Organ of Corti; Outer Hair Cells; Oxidative Stress; Pathway interactions; Permeability; Pharmaceutical Preparations; Phase; Pilot Projects; Platinum; Presbycusis; Publications; Publishing; Reactive Oxygen Species; Recovery; Regimen; Research; Resolution; Roentgen Rays; Role; SOD2 gene; Signal Pathway; Sirtuins; Site; Stria Vascularis; Structure; Synapses; System; Testing; Therapeutic Effect; Toxic effect; Transgenic Organisms; Western Blotting; antitumor drug; antitumor effect; biological adaptation to stress; carcinogenesis; chemotherapy; cisplatin induced hearing loss; clinically significant; confocal imaging; cytokine; early onset; experimental study; hearing impairment; honokiol; improved; inhibitor; insight; member; meter; microCT; mouse model; neoplastic cell; neuron loss; otoacoustic emission; ototoxicity; oxidative damage; polyphenol; prevent; protective effect; response; spiral ganglion; tumor

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.

项目摘要 /摘要 顺铂是一种有效的抗肿瘤药物，用于约40％的癌症化学疗法方案以及 其他基于铂的药物。不幸的是，顺铂也诱导多种不良毒性作用 例如耳毒性，造成约1万新的听力障碍案件 仅在美国，每年一次。顺铂引起的听力损失（CIHL）为 与活性氧（ROS）的产生有关，造成人工耳蜗，特别是 外毛细胞的丧失（OHC）。在这方面，用作自由基清除剂的抗氧化剂 提出用于治疗CIHL）。但是，抗氧化剂会产生很多问题，例如 停用顺铂并保护肿瘤细胞。迄今为止，没有有效的CIHL临床治疗 已获得批准。与抗氧化剂不同，Honokiol（HNK）是多功能分子 这既可以保护正常细胞免受氧化损伤，又可以增强 顺铂。 HNK对CIHL的保护作用在我们最近的出版物中得到了验证。这 机制与抗ROS的关键调节剂Sirtuins的激活有关 细胞中的系统。 Sirtuin家族由7个脱乙酰基酶组成，在 不同的细胞内位置，包括细胞质（SIRT1，2），线粒体（SIRT3-5）和 核（SIRT1、2、6、7），并形成用于ROS排毒的内在网络。 在这项研究中，Sirtuin家族在HNK对CIHL的保护作用中的作用将是 进一步调查。首先，HNK对CIHL的听力保护作用和激活 在接受化学疗法的肿瘤轴承小鼠模型中，将进一步验证sirtuins的。 其次，将在SIRT1缺乏模型中验证胞质Sirtuins（SIRT1）的重要性。 第三，线粒体Sirtuins（Sirt3和Sirt5）的作用及其潜在补偿 将使用SIRT3基因敲除小鼠和异氯酸酯脱氢酶2敲除核 老鼠。将测量听觉的脑干响应和失真产品耳声发射 评估听力功能。 X射线荧光显微镜将用于验证分布 内耳中的铂。免疫染色，共聚焦成像和X射线微型计算 断层扫描将用于研究形态学变化，例如OHC丢失。更多 将获得对CIHL机制及其保护的全面理解。 通过使用HNK为人类测试奠定基础，该项目具有极大的临床意义 用于化学疗法的听力保护。此外，拟议的研究还将提供洞察力 进行听力保护，以防止其他类型的听力障碍，例如噪声引起的，药物 - 诱导和与年龄有关的听力损失。