Hearing Protection in Cisplatin Chemotherapy

顺铂化疗中的听力保护

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要顺铂是一种强效抗肿瘤药物，与化疗药物一起用于约 40% 的癌症化疗方案其他铂类药物。不幸的是，顺铂还会引起多种不良毒性作用例如耳毒性，导致约 100-30 万新的听力障碍病例仅在美国，每年就有癌症患者出现这种情况。顺铂引起的听力损失（CIHL）是与活性氧 (ROS) 的产生有关，导致耳蜗损伤，特别是外毛细胞（OHC）的损失。在这方面，抗氧化剂充当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，例如使顺铂失活并保护肿瘤细胞。迄今为止，临床上尚无针对CIHL的有效治疗方法已获批准。与抗氧化剂不同，和厚朴酚（HNK）是一种多功能分子既可以保护正常细胞免受氧化损伤，又可以增强抗肿瘤作用顺铂。 HNK 对 CIHL 的保护作用在我们最近的出版物中得到了证实。这机制与抗ROS的关键调节因子sirtuins的激活有关细胞内的系统。 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) 和细胞核（SIRT1、2、6、7）并形成 ROS 解毒的内在网络。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。一、HNK对CIHL的听力保护作用及激活 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，细胞质去乙酰化酶 (SIRT1) 的重要性将在 SIRT1 缺陷模型中得到验证。第三，线粒体sirtuins（SIRT3和SIRT5）的作用及其潜在的补偿作用彼此将使用 SIRT3 敲除小鼠和异柠檬酸脱氢酶 2 敲除小鼠进行验证老鼠。将测量听觉脑干反应和失真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内耳中的铂金。免疫染色、共焦成像和 X 射线微计算断层扫描将用于研究 OHC 损失等形态变化。一个更多全面了解CIHL的机制及其保护。该项目具有重要的临床意义，为HNK的人体试验奠定了基础用于化疗时的听力保护。此外，拟议的研究还将提供见解听力保护以防止其他类型的听力损伤，例如噪音引起的听力损伤、药物引起的听力损伤诱发性和年龄相关的听力损失。