Use of Curcumin and Flaxsseed in Radiation Pneumonopathy

描述（由申请人提供）：胸部放射治疗的有效性受到肺部组织对根除恶性细胞所需的照射剂量的敏感性的极大限制。临床上显著的放射性肺损伤，如肺炎样炎症和晚期纤维化，发生在高达30%的肺癌放疗患者和约10-15%的其他胸部肿瘤患者中。然而，保护“正常”肺实质免受不可接受的辐射损伤的需要损害了提供肿瘤杀伤放疗剂量的能力。活性氧（ROS），如电离辐射诱导的大量活性氧，被认为在纤维化肺病的发病机制中起着重要作用。然而，从氧化组织损伤到晚期放射纤维化的分子途径尚不清楚，目前还没有可用的自由基清除剂来提供可接受水平的肺放射保护而不产生严重的副作用。我们和其他人已经证明抗氧化酶治疗可以减轻辐射诱导的纤维化肺疾病。最近发现的nf - e2相关因子2 （Nrf2）是抗氧化反应元件（ARE）的关键转录调控因子，可介导细胞抗氧化剂和解毒蛋白的诱导。我们有初步数据支持姜黄素和亚麻籽木脂素是安全的，天然存在的，植物衍生的，具有抗氧化，抗炎和抗癌特性的多效化合物，激活Nrf2/ARE通路并介导抗氧化和细胞保护基因的转录。我们假设协调诱导Nrf2/ARE调节的抗氧化基因可能是一种新的治疗策略，以减轻放射性肺病。本研究将使用新的分子方法确定这些药物激活Nrf2的两种潜在机制：激酶介导的磷酸化和增加Nrf2蛋白稳定性（特异性目标1），并将在Nrf2转基因动物和野生型对照中使用姜黄素和亚麻籽膳食配方，探索这些药物在放射性肺损伤小鼠模型中的潜在放射保护功效（特异性目标2）。这项工作关于作用机制的发现及其在实验动物的肺部辐射防护中的作用，以及这些植物化学物质可以安全地施用于人类的知识，将有助于设计未来癌症治疗背景下的临床试验。

DESCRIPTION (provided by applicant): The usefulness of thoracic radiotherapy is greatly limited by the sensitivity of the lung tissue to irradiation doses necessary to eradicate malignant cells. Clinically significant radiation lung injury, such as pneumonia- like inflammation and late stage fibrosis, occurs in up to 30% of patients irradiated for lung cancer and about 10-15% of other thoracic oncology patients. The need, however, to protect "normal" lung parenchyma from unacceptable radiation injury compromises the ability to deliver tumoricidal radiotherapy doses. Reactive oxygen species (ROS) such as those induced in large quantities by ionizing radiation are believed to contribute significantly to the pathogenesis of fibrotic lung disease. However the molecular pathways from the oxidative tissue insult to late radiation fibrosis are unclear and at this time, there is no available free radical scavenger to offer acceptable levels of pulmonary radioprotection without serious side effects. We and others have shown that antioxidant enzyme therapy alleviates radiation-induced fibrotic lung disease. The recently discovered NF-E2-related factor 2 (Nrf2), a key transcriptional regulator for antioxidant response element (ARE) mediates induction of cellular antioxidants and detoxifying proteins. We have preliminary data to support that curcumin and flaxseed lignans, safe, naturally occurring, plant-derived, pleiotropic compounds with known antioxidant, anti-inflammatory and anticarcinogenic characteristics, activate the Nrf2/ARE pathway and mediate transcription of antioxidant and cytoprotective genes. We hypothesize that coordinate induction of Nrf2/ARE regulated antioxidant genes may be a novel therapeutic strategy to alleviate radiation pneumonopathy. This study will determine using novel molecular methodologies, two potential mechanisms by which these agents activate Nrf2: kinase-mediated phosphorylation and increased Nrf2 protein stability (Specific Aim 1) and will explore the potential pulmonary radioprotective efficacy of these agents in a well-established murine model of radiation lung injury using dietary formulations of curcumin and flaxseed in Nrf2 trangenic animals and wild type controls (Specific Aim 2). The findings of this work regarding mechanism of action and their usefulness in lung radioprotection in experimental animals and the knowledge that these phytochemicals can be safely administered to humans will enable the design of future clinical trials in the context of cancer treatment.