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(申请人提供)：尽管世界各地禁止使用石棉，但不幸的是，家庭和环境中的石棉暴露仍然存在。接触石棉纤维与恶性间皮瘤(MM)和肺癌(LC)的发展有关；然而，与石棉相关的疾病的发病机制复杂，仍然知之甚少。与接触石棉有关的肺部炎症在动物模型和人类中都有显示。更多的研究表明，石棉纤维产生活性氧和氮物种(ROS/RNS)，并导致蛋白质和DNA的氧化和/或亚硝化。除了破坏大分子外，这些氧化剂还在启动许多与细胞凋亡、炎症和增殖相关的信号转导通路中发挥重要作用。不幸的是，虽然向接触石棉的个人提供了医疗监测或经济补偿，但目前没有采取任何措施来降低他们患癌症的风险。事实上，石棉相关癌症的潜伏期很长，从LC的10年到MM的长达50年不等，这为化学预防策略的使用提供了广泛的窗口，人们可以通过使用天然或合成试剂进行干预，以拦截或防止因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接触石棉的个人的癌症风险，这一领域的临床试验的匮乏突显了干预措施的需求尚未得到满足。我们的小组评估了全谷物亚麻籽在小鼠氧化性肺损伤模型中的作用，并将其归因于组织保护特性 主要是其木脂素成分具有抗氧化、抗炎和抗纤维化作用。这个 亚麻籽中最具生物活性的木脂素是一种双酚类化合物--木脂素二糖苷(SDG)。重要的是，添加SDG的饮食有力地减轻了辐射毒性，表现为慢性炎症、氧化组织损伤和纤维化，当在最初的辐射伤害发生很长时间后给药给药时。因此，我们假设SDG同样会通过干扰正在进行的损害过程的启动和传播来消除石棉毒性，这些过程最终将导致肺纤维化、慢性炎症和氧化组织损伤，这些条件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，用来评估SDG在两种石棉诱导的多发性骨髓瘤小鼠模型中的作用。在特定目标1中，我们将在SV40标签和NF2+/-小鼠石棉炎症模型中测试亚麻籽和SDG木脂素的抗炎作用；在特定目标2中，我们将测试在钝化MM形成和提高生存方面的癌症化学预防作用。如果我们的干预措施在任何一种模型中被证明在抑制炎症、延缓恶性肿瘤的发生或减轻肿瘤负担方面有效，我们将继续进行机制研究，以评估暴露于石棉的间皮细胞和巨噬细胞中SDG在炎症小体激活、细胞凋亡、DNA损伤、ROS/RNS生成和信号通路激活方面的作用(Fos和Jun家族)。