Oral Epigallocatechin Gallate (EGCG) for Treatment of Cisplatin Ototoxicity

顺铂是一种广泛用于治疗多种人类癌症的化学治疗剂。但 这种药物的治疗益处受到剂量限制性副作用的影响， 和神经毒性。通过听力测定研究评估的顺铂引起的听力障碍的发生率， 75- 100%。在儿科人群中，顺铂用于治疗神经母细胞瘤和中枢神经系统肿瘤， 系统恶性肿瘤，听力损失可能会阻碍儿童的语言，认知和社会发展。其他 药物，如卡铂和奥沙利铂，已经成为顺铂的替代品，但它们的有效性是有限的。 仅限于少数几种癌症，并且它们产生一致的神经病变。顺铂被证明是更有效的比 卡铂治疗非小细胞肺癌的副作用似乎相当。 因此，顺铂仍然保持其作为用于各种癌症的化疗方案的组分的重要性。 虽然顺铂的化学治疗功效的机制似乎是DNA烷基化，但是DNA烷基化的产生可能与顺铂的化学治疗功效有关。 经由NOX 3 NADPH氧化酶的活性氧（ROS）似乎对于介导顺铂耳毒性至关重要， 肾毒性这激发了使用抗氧化剂作为耳保护剂的兴趣。这种方法的局限性， 含硫醇的抗氧化剂可能干扰顺铂的抗肿瘤功效。我们最近 显示了信号转导和转录激活因子1（STAT 1）将ROS（来自顺铂）偶联到 炎症级联反应，加剧听力损失。我们还表明，STAT 1的敲低（通过siRNA） 预防顺铂引起的听力损失。此外，我们的初步数据显示，表没食子儿茶素没食子酸酯 表没食子儿茶素没食子酸酯（EGCG），绿色茶中最丰富的儿茶素和STAT 1的抑制剂保护顺铂耳毒性。 有趣的是，EGCG还激活STAT 3，这是一种与细胞存活相关的转录因子。这些双重机制 本拨款建议书将更详细探讨表没食子儿茶素没食子酸酯的耳保护作用。EGCG的另一个优点 它具有固有的抗癌特性，并且不干扰顺铂化疗功效 在最初的研究中。本提案的目的是确定口服表没食子儿茶素没食子酸酯对顺铂的疗效 大鼠耳毒性和肾毒性（具体目的1）。保护作用的机制 表没食子儿茶素没食子儿茶素没食子酸酯对抗顺铂耳毒性，重点是STAT 1和STAT 3通路和基因表达 分析，将在具体目标2中进行审查。特定目标3将确定潜在的抗肿瘤干扰 在异种移植小鼠模型中通过表没食子儿茶素没食子酸酯（EGCG）对抗不同的肿瘤细胞。本研究提供的结果将 更好地了解EGCG治疗顺铂耳毒性和肾毒性的效用， 可以支持其在癌症患者中的治疗用途。此外，这项研究应该扩大我们的知识 关于STAT 1/STAT 3平衡在毛细胞存活中的重要性。

Cisplatin is a widely used chemotherapeutic agent for the treatment of a variety of human cancers. However, the therapeutic benefits of this drug are compromised by dose limiting side effects such as ototoxicity, nephrotoxicity and neurotoxicity. The incidence of cisplatin-induced hearing deficits, assessed by audiometric studies, range from 75-100%. In the pediatric population, where cisplatin is used to treat neuroblastomas and central nervous system malignancies, loss of hearing could hamper speech, cognition and social development of the child. Other drugs, such as carboplatin and oxaliplatin, have emerged as alternatives to cisplatin, but their usefulness is limited to a few cancers and they produce consistent neuropathies. Cisplatin is shown to be more effective than carboplatin in treating non-small-cell lung cancer even though the side effects of the two drugs appear equivalent. Thus, cisplatin still retains its importance as a component of the chemotherapeutic regimen for various cancers. While the mechanism of chemotherapeutic efficacy of cisplatin appears to be DNA alkylation, the generation of reactive oxygen species (ROS) via NOX3 NADPH oxidase appears critical for mediating cisplatin ototoxicity and nephrotoxicity. This has stimulated interest for using antioxidants as otoprotectants. A limitation of this approach, however, is that thiol-containing antioxidants could interfere with cisplatin antitumor efficacy. We have recently shown that signal transducer and activator of transcription 1 (STAT1) couples ROS (from cisplatin) to the inflammatory cascade, which exacerbates hearing loss. We also shown that knockdown of STAT1 (by siRNAs) protects against cisplatin-induced hearing loss. Moreover, our preliminary data show that epigallocatechin gallate (EGCG), the most abundant catechin in green tea and an inhibitor of STAT1 protects against cisplatin ototoxicity. Interestingly, EGCG also activates STAT3, a transcription factor linked to cell survival. These dual mechanisms of otoprotection by EGCG would be explored in more detail in this grant proposal. An added advantage of EGCG is that it possesses intrinsic anticancer properties and does not interfere with cisplatin chemotherapeutic efficacy in initial studies. The goals of this proposal are to determine the efficacy of oral EGCG against cisplatin ototoxicity and nephrotoxicity in rats (Specific aims 1). The mechanisms underlying the protective action of EGCG against cisplatin ototoxicity, focusing on the STAT1 and STAT3 pathways and gene expression analysis, will be examined in Specific aim 2. Specific aim 3 will determine potential antitumor interference by EGCG against different tumor cells in xenograft mouse models. The results provided in this study would provide a better understanding of the utility of EGCG for the treatment of cisplatin oto- and nephrotoxicity and could support its therapeutic use in cancer patients. Furthermore, this study should expand our knowledge concerning the importance of STAT1/STAT3 balance in hair cell survival.