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组织对根除恶性细胞所需的辐射剂量的敏感性的极大限制。临床上重要的放射性肺损伤，如肺炎样炎症和晚期纤维化，发生在高达30%的肺癌患者和大约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，损害了提供杀瘤放射剂量的能力。活性氧(ROS)，如电离辐射诱导的大量ROS，被认为在纤维化肺疾病的发病机制中起重要作用。然而，从氧化组织损伤到晚期放射性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的水平的肺辐射保护，而不会产生严重的副作用。我们和其他人已经证明，抗氧化酶疗法可以缓解辐射诱导的纤维化肺部疾病。最近发现的核因子-E2相关因子2(Nrf2)是抗氧化反应元件(ARE)的关键转录调节因子，介导细胞内抗氧化剂和解毒蛋白的诱导。我们有初步的数据支持，姜黄素和亚麻籽木脂素，安全的，自然存在的，植物来源的，具有已知的抗氧化，抗炎和抗癌特性的多效性化合物，激活Nrf2/ARE途径，并介导抗氧化和细胞保护基因的转录。我们推测，协调诱导Nrf2/Are调节的抗氧化基因可能是缓解放射性肺炎的一种新的治疗策略。这项研究将使用新的分子方法确定这些药物激活Nrf2的两个潜在机制：激酶介导的磷酸化和增加Nrf2蛋白的稳定性(特定目标1)，并将在Nrf2转基因动物和野生型对照(特定目标2)中使用姜黄素和亚麻籽饮食配方建立的放射性肺损伤小鼠模型中探索这些药物的潜在肺辐射防护效果。这项关于作用机制及其在实验动物肺部辐射防护中的有用性的工作发现，以及这些植物化学物质可以安全地用于人类的知识，将使未来癌症治疗方面的临床试验的设计成为可能。

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.