Hearing Protection in Cisplatin Chemotherapy

点击翻译按钮获取中文摘要

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.