Mesothelioma inhibition by secoisolariciresinol diglucoside (SDG)

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的情况仍然存在。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是复杂的，仍然知之甚少。与石棉接触有关的肺部炎症已在动物模型和人类中得到证实。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的氧化和/或亚硝基化。除了破坏大分子外，这些氧化剂在许多与细胞凋亡、炎症和增殖相关的信号转导途径的启动中发挥重要作用。不幸的是，虽然对石棉接触者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50年不等，这为化学预防策略的使用提供了一个很宽的窗口，人们可以用天然或合成药物进行干预，以拦截或预防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石棉接触者患癌症的风险，这一领域临床试验的缺乏凸显了干预的需求尚未得到满足。本研究小组在小鼠氧化性肺损伤（如辐射毒性）模型中评估了全麦亚麻籽，并将其归因于其组织保护特性

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).