Oral Epigallocatechin Gallate (EGCG) for Treatment of Cisplatin Ototoxicity

口服表没食子儿茶素没食子酸酯（EGCG）治疗顺铂耳毒性

• 批准号: 10163157
• 负责人: Vickram Ramkumar
• 金额: $ 36.72万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163157
• 关键词: 4 hydroxynonenal; Acute Kidney Failure; Adopted; Affect; Aldehydes; Amifostine; Aminoglycoside Antibiotics; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Apoptotic; Applications Grants; Binding; Breast Cancer Cell; Buffers; Cancer Patient; Carboplatin; Cardiovascular Diseases; Catechin; Cell Cycle; Cell Death; Cell Survival; Cells; Cellular Membrane; Central Nervous System Neoplasms; Child; Child Development; Childhood; Cisplatin; Cochlea; Cognition; Colon Carcinoma; Complement; Couples; Cysteine; DNA Alkylation; Data; Development; Diabetes Mellitus; Dose; Dose-Limiting; Drug Side Effects; Drug Targeting; Epigallocatechin Gallate; Equilibrium; Future; Gene Expression Profiling; Generations; Genes; Genetic Transcription; Goals; Green tea; Hair Cells; Head and Neck Cancer; Human; Hydroxyl Radical; Incidence; Inflammation; Inflammatory; Knowledge; Link; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methionine; Mitogen-Activated Protein Kinases; Mutagens; NADPH Oxidase; Natural Products; Neuraxis; Neuroblastoma; Neurodegenerative Disorders; Neuropathy; Noise; Non-Small-Cell Lung Carcinoma; Obesity; Oral; Ovarian; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Platinum; Population; Process; Production; Property; Protein Isoforms; Rattus; Reactive Oxygen Species; Regimen; Role; SCID Mice; STAT1 protein; STAT3 gene; Serine; Site; Small Interfering RNA; Social Development; Solid Neoplasm; Source; Speech; Sulfhydryl Compounds; TP53 gene; Therapeutic; Therapeutic Uses; Tissue Microarray; Toxic effect; Xenograft procedure; aminoglycoside-induced ototoxicity; anti-cancer; antioxidant therapy; base; cancer cell; cancer therapy; cell killing; chemotherapeutic agent; chemotherapy; cisplatin induced hearing loss; effective therapy; effectiveness testing; hearing impairment; hearing loss treatment; immunodeficient mouse model; improved; inhibitor/antagonist; interest; knock-down; mouse model; neoplastic cell; nephrotoxicity; neurotoxicity; novel; otoprotectant; ototoxicity; oxaliplatin; refractory cancer; side effect; small molecule inhibitor; sodium thiosulfate; stem; transcription factor; transcriptome sequencing; treatment group; treatment response

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.

顺铂是一种广泛使用的化疗药物，用于治疗多种人类癌症。然而， 该药物的治疗效果因剂量限制性副作用（例如耳毒性、肾毒性）而受到损害 和神经毒性。通过听力测定研究评估顺铂引起的听力缺陷的发生率，范围 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瘤 系统恶性肿瘤、听力损失可能会妨碍儿童的言语、认知和社会发展。其他 卡铂和奥沙利铂等药物已作为顺铂的替代品出现，但它们的用途是 仅限于几种癌症，并且它们会产生一致的神经病变。顺铂被证明比顺铂更有效 卡铂治疗非小细胞肺癌，尽管这两种药物的副作用看起来相当。 因此，顺铂仍然保留其作为各种癌症化疗方案的组成部分的重要性。 虽然顺铂的化疗功效机制似乎是 DNA 烷基化，但 通过 NOX3 NADPH 氧化酶产生的活性氧 (ROS) 对于介导顺铂耳毒性和 肾毒性。这激发了人们对使用抗氧化剂作为耳保护剂的兴趣。这种方法的局限性， 然而，含硫醇的抗氧化剂可能会干扰顺铂的抗肿瘤功效。我们最近有 表明信号转导子和转录激活子 1 (STAT1) 将 ROS（来自顺铂）与 炎症级联反应，加剧听力损失。我们还证明了 STAT1 的敲低（通过 siRNA） 防止顺铂引起的听力损失。此外，我们的初步数据表明表没食子儿茶素没食子酸酯 (EGCG) 是绿茶中最丰富的儿茶素，也是 STAT1 的抑制剂，可防止顺铂耳毒性。 有趣的是，EGCG 还能激活 STAT3，一种与细胞存活相关的转录因子。这些双重机制 本拨款提案将更详细地探讨 EGCG 的耳保护作用。 EGCG 的另一个优势 其优点是它具有内在的抗癌特性，并且不会干扰顺铂的化疗效果 在初步研究中。该提案的目标是确定口服 EGCG 对抗顺铂的功效 大鼠的耳毒性和肾毒性（具体目标 1）。保护作用的机制 EGCG 对抗顺铂耳毒性的研究，重点关注 STAT1 和 STAT3 通路和基因表达 分析，将在特定目标 2 中进行检查。特定目标 3 将确定潜在的抗肿瘤干扰 通过 EGCG 对抗异种移植小鼠模型中的不同肿瘤细胞。本研究提供的结果将 更好地了解 EGCG 在治疗顺铂耳毒性和肾毒性方面的用途， 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 STAT1/STAT3 平衡在毛细胞存活中的重要性。