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: 8695307
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 6.75万
• 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/8695307
• 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，家庭和环境中石棉的暴露仍然存在。接触石棉纤维与恶性间皮瘤 (MM) 和肺癌 (LC) 的发生有关；然而，石棉相关疾病的发病机制很复杂，人们仍然知之甚少。在动物模型和人类中都显示出与石棉接触相关的肺部炎症。其他研究表明，石棉纤维会产生活性氧和活性氮 (ROS/RNS)，并导致蛋白质和 DNA 氧化和/或亚硝基化。除了破坏大分子之外，此类氧化剂还在启动与细胞凋亡、炎症和增殖相关的众多信号转导途径中发挥重要作用。不幸的是，虽然石棉暴露者可以获得医疗监测或经济补偿，但目前还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，LC 为 10 年，MM 为 50 年，这为化学预防策略的使用提供了广阔的空间，人们可以使用天然或合成药物进行干预，以拦截或预防由于接触而导致的恶性转化。值得注意的是，目前还没有采取任何措施来降低接触石棉的个体患癌症的风险，而且该领域临床试验的缺乏凸显了干预需求尚未得到满足。我们的小组在氧化性肺损伤（例如辐射毒性）的小鼠模型中评估了全麦亚麻籽，并归因于其组织保护特性 主要与其木酚素成分的抗氧化、抗炎、抗纤维化作用有关。这 亚麻籽中的主要生物活性木酚素是开环异落叶松树脂醇二葡萄糖苷 (SDG)，一种双酚类物质。重要的是，在最初的辐射损伤发生后很长时间内，向小鼠施用补充 SDG 的饮食可有效减轻表现为慢性炎症、氧化组织损伤和纤维化的辐射毒性。因此，我们假设 SDG 将通过干扰持续破坏过程的启动和传播来消除石棉毒性，这些过程最终会导致肺纤维化、慢性炎症和氧化组织损伤，这些情况被发现与多发性骨髓瘤的发展有关。为了测试这一点，我们设计了两个目标，以评估 SDG 在石棉诱导的 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 SV40 TAg 和 NF2 +/- 小鼠石棉炎症模型中的抗炎作用，在具体目标 2 中，我们将测试在抑制 MM 形成和提高存活率方面的癌症化学预防作用。如果我们的干预措施在任何模型中被证明能有效抑制炎症、延缓恶性肿瘤的发生或减轻肿瘤负荷，我们将进行机制研究，以评估石棉暴露的间皮细胞和巨噬细胞中 SDG 的炎症小体激活、细胞凋亡、DNA 损伤、ROS/RNS 生成和信号通路激活（Fos 和 Jun 家族）。