Biomedical Project 5 - Chemoprevention of Asbestos-induced Lung Diseases

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ABSTRACT It has now been clearly established in both animal models and in humans that inhalation of asbestos fibers can lead to neoplastic diseases such as malignant mesothelioma (MM) and lung cancer. This is an important ongoing problem, since asbestos is still in used in many countries around the world and there is also a large pool of previously exposed individuals who are at risk for cancer. There is currently no effective screening or chemopreventive approach for these at-risk populations. Given that recent studies have indicated that the pathogenesis of asbestos-induced cancers is due to chronic inflammation and oxidative tissue damage caused by persistent asbestos fibers, a well-tolerated and safe agent with anti-inflammatory AND anti-oxidant properties could thus potentially be used to prevent the development of MM in asbestos exposed populations. Based on preliminary findings, we have found that flaxseed lignans are safe, non-toxic compounds that have potent anti-inflammatory and anti-oxidant properties. We therefore hypothesize that that flaxseed or enriched flaxseed lignans could function as safe, non-toxic chemopreventive agents in asbestos- induced mesothelioma. The goal of this grant is to provide data needed as the first steps to test and validate this hypothesis. To achieve our goal, we propose to: 1) Evaluate the ability of the active lignan in flaxseed, Secoisolariciresinol diglucoside (SDG), to interfere with asbestos-induced ROS generation, inflammasome activation, and reactive oxygen species generation in macrophages and mesothelial cells in vitro. 2) Evaluate the ability of wholegrain flaxseed or flaxseed-lignan complex given in diets to prevent acute asbestos-induced inflammation and oxidative damage in the mesothelial SV40 T-Antigen and the Nf2+/mut;Cdkn2a+/mut asbestos-induced malignant mesothelioma mouse models, and 3) Evaluate the ability of wholegrain flaxseed or flaxseed-derived lignan SDG given in diets to prevent asbestos-induced MM formation and death in these same mouse models. If our studies show efficacy with safety, the natural extension of our work would be a toxicity and biomarker trial in which patients with heavy asbestos exposure who also had biomarkers of exposure (identified above and in Project 6) would be given flaxseed or the lignan formulation and changes in biomarkers identified. If we observed clear changes in this trial, a larger chemoprevention trial in high risk populations could be considered. We will interact with closely with three projects in this Superfund Proposal including testing remediated asbestos from Project 1, working closely with the animal model studies in Project 4, and taking advantage of the biomarker work in Project 6. We will also interact significantly with the Administration and Biostatistics Cores of the SF proposal and the Biomarker Core of the CEET.