Mesothelioma inhibition by secoisolariciresinol diglucoside (SDG)

开环异落叶松树脂醇二葡萄糖苷 (SDG) 抑制间皮瘤

• 批准号: 8598613
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 6.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598613
• 关键词: Acute; Alveolar Macrophages; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Area; Asbestos; Asbestos-Related Malignant Neoplasm; Australia; Botanicals; Breathing; Cells; Cereals; Cessation of life; Chemopreventive Agent; Chronic; Clinical Trials; DNA; DNA Damage; Development; Diet; Disease; Environmental Exposure; Epithelial Cells; Exhibits; Exposure to; Family; Fiber; Fibrosis; Financial compensation; Flax; Foxes; Free Radical Scavengers; Generations; Genes; Human; Individual; Inflammation; Inflammatory; Institutes; Intercept; Intervention; Lead; Lignans; Link; Lung; Lung diseases; Malignant - descriptor; Malignant Neoplasms; Malignant mesothelioma; Malignant neoplasm of lung; Medical Surveillance; Mesothelial Cell; Mesothelioma; Modality; Modeling; Molecular; Mus; Nitrogen; Occupational Exposure; Oxidants; Oxygen; Particulate; Pathogenesis; Peritoneal; Philadelphia; Play; Pneumonia; Preclinical Testing; Preventive; Process; Property; Proteins; Radiation; Radiation Toxicity; Reactive Oxygen Species; Rodent Model; Role; Signal Pathway; Signal Transduction Pathway; Simian virus 40; Testing; Tissues; Toxic effect; Tumor Burden; cancer cell; cancer prevention; cancer risk; carcinogenesis; cell injury; cell transformation; chemokine; cytokine; design; dietary supplements; environmental carcinogenesis; flaxseed lignan; human disease; macromolecule; macrophage; mouse model; novel; oxidation; pollutant; prevent; public health relevance; secoisolariciresinol diglucoside; stressor; tumor

DESCRIPTION (provided by applicant): Despite worldwide banning of asbestos use, domestic and environmental exposure to asbestos unfortunately persists. Exposure to asbestos fibers has been linked to the development of malignant mesothelioma (MM) and lung cancer (LC); however, the pathogenesis of asbestos-related diseases is complicated and still poorly understood. Pulmonary inflammation related to asbestos exposure has been shown in both animal models and humans. Additional studies revealed that asbestos fibers generate reactive oxygen and nitrogen species (ROS/RNS) and cause oxidation and/or nitrosylation of proteins and DNA. In addition to damaging macromolecules, such oxidants play important roles in the initiation of numerous signal transduction pathways that are linked to apoptosis, inflammation, and proliferation. Unfortunately, while asbestos-exposed individuals are offered medical surveillance or financial compensation, but nothing is currently being undertaken to decrease their cancer risk. In fact the long latency of asbestos-related cancers ranging from 10 years for LC and up to 50 years for MM, allows a wide window for chemopreventive strategies to be used whereby one can intervene with natural or synthetic agents to intercept or prevent malignant transformation due to exposure. Remarkably, nothing is currently being done to lower cancer risk to asbestos-exposed individuals and the scarcity of clinical trials in this area underscores the unmet need for intervention. Our group has evaluated wholegrain flaxseed in murine models of oxidative lung damage such as radiation toxicity and attributed its tissue protective properties mainly to the antioxidant, anti-inflammatory and anti-fibrotic effects of its lignan component. The predominant bioactive lignan in flax seed is Secoisolariciresinol Diglucoside (SDG), a biphenolic agent. Importantly, SDG-supplemented diets robustly mitigated radiation toxicity manifested as chronic inflammation, oxidative tissue damage and fibrosis when administered to mice long after the initial radiation insult occurred. We therefore, hypothesize that SDG will similarly abrogate asbestos toxicity by interfering with initiation and propagation of ongoing damaging processes that would ultimately lead to lung fibrosis, chronic inflammation and oxidative tissue damage, conditions found to be linked to MM development. To test this, we designed two Aims whereby the action of SDG in 2 mouse models of asbestos-induced MM will be evaluated. In Specific Aim 1 we will test anti-inflammatory effects of flaxseed and SDG lignan diets in the SV40 TAg and the NF2 +/- mouse model of asbestos-inflammation and in Specific Aim 2 we will test the cancer chemopreventive effects in blunting MM formation and boosting survival. If our intervention proves effective in inhibiting inflammation, delaying the onset of malignancy or decreasing tumor burden in any of the models, we will pursue mechanistic studies to evaluate SDG in asbestos-exposed mesothelial cells and macrophages for inflammasome activation, apoptosis, DNA damage, ROS/RNS generation and signaling pathway activation (Fos and Jun families).

描述（由申请人提供）：尽管世界范围内禁止使用石棉，但不幸的是，家庭和环境暴露于石棉仍然存在。接触石棉纤维与恶性间皮瘤（MM）和肺癌（LC）的发展有关;然而，石棉相关疾病的发病机制很复杂，仍然知之甚少。与石棉暴露相关的肺部炎症已在动物模型和人类中显示。进一步的研究表明，石棉纤维产生活性氧和氮物质（ROS/RNS），并导致蛋白质和DNA的氧化和/或亚硝基化。除了破坏大分子外，这些氧化剂在启动与细胞凋亡、炎症和增殖相关的许多信号转导途径中起重要作用。不幸的是，虽然接触石棉的个人得到了医疗监督或经济补偿，但目前没有采取任何措施来降低他们的癌症风险。事实上，石棉相关癌症的潜伏期很长，从LC的10年到MM的50年不等，这为使用化学预防策略提供了一个广阔的窗口，人们可以通过天然或合成药物进行干预，以阻止或预防由于暴露而导致的恶性转化。值得注意的是，目前没有采取任何措施来降低石棉暴露个体的癌症风险，并且该领域临床试验的稀缺突出了未满足的干预需求。我们的研究小组已经评估了全谷亚麻籽在小鼠模型中的氧化性肺损伤，如辐射毒性，并归因于其组织保护特性 主要涉及其木脂素成分的抗氧化、抗炎和抗纤维化作用。的 亚麻籽中主要的生物活性木脂素是开环异落叶松树脂酚二葡糖苷（SDG），一种双酚试剂。重要的是，当在初始辐射损伤发生后很久给予小鼠时，补充SDG的饮食强烈减轻了表现为慢性炎症，氧化组织损伤和纤维化的辐射毒性。因此，我们假设SDG将通过干扰正在进行的破坏性过程的启动和传播来类似地消除石棉毒性，这些过程最终导致肺纤维化、慢性炎症和氧化性组织损伤，这些条件被发现与MM发展有关。为了测试这一点，我们设计了两个目标，其中将评估SDG在2种石棉诱导的MM小鼠模型中的作用。在具体目标1中，我们将测试亚麻籽和SDG木脂素饮食在SV 40 TAg和NF 2 +/-石棉炎症小鼠模型中的抗炎作用，在具体目标2中，我们将测试癌症化学预防作用在钝化MM形成和提高存活率方面的作用。如果我们的干预在任何模型中被证明有效抑制炎症、延迟恶性肿瘤的发作或降低肿瘤负荷，我们将进行机制研究以评估暴露于石棉的间皮细胞和巨噬细胞中的SDG的炎性小体活化、凋亡、DNA损伤、ROS/RNS产生和信号传导途径活化（Fos和Jun家族）。