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.

Public Health Relevance

Malignant mesothelioma (MM) is a devastating and lethal malignancy that is associated with asbestos exposure. MM development is believed to be associated with chronic oxidative damage and chronic inflammation. Flaxseed, via the action of its lignan secoisolariciresinol diglucoside (SDG), a polyphenolic compound found in flaxseed, has numerous potentially beneficial effects including cardioprotection, anti- oncogenesis, as well as anti-oxidant and anti-inflammatory from work originating in our lab at the University of Pennsylvania making it a good candidate chemopreventive tool for MM. We propose here to examine the potential lung chemopreventive effects of flaxseed and its lignan in mouse models of experimental asbestos-induced MM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
1P42ES023720-01
Application #
8651092
Study Section
Special Emphasis Panel (ZES1-LKB-K (S))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$298,285
Indirect Cost
$111,857
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Salamatipour, Ashkan; Mohanty, Sanjay K; Pietrofesa, Ralph A et al. (2016) Asbestos Fiber Preparation Methods Affect Fiber Toxicity. Environ Sci Technol Lett 3:270-274
Clapp, Justin T; Roberts, Jody A; Dahlberg, Britt et al. (2016) Realities of environmental toxicity and their ramifications for community engagement. Soc Sci Med 170:143-151
Pietrofesa, Ralph A; Velalopoulou, Anastasia; Lehman, Stacey L et al. (2016) Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel. Int J Mol Sci 17:
Frey, Alexander J; Wang, Qingqing; Busch, Christine et al. (2016) Validation of highly sensitive simultaneous targeted and untargeted analysis of keto-steroids by Girard P derivatization and stable isotope dilution-liquid chromatography-high resolution mass spectrometry. Steroids 116:60-66
Pietrofesa, Ralph A; Velalopoulou, Anastasia; Arguiri, Evguenia et al. (2016) Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice. Carcinogenesis 37:177-87
Guo, Lili; Worth, Andrew J; Mesaros, Clementina et al. (2016) Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. Rapid Commun Mass Spectrom 30:1835-45
Kadariya, Yuwaraj; Menges, Craig W; Talarchek, Jacqueline et al. (2016) Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma. Cancer Prev Res (Phila) 9:406-14
Kadariya, Yuwaraj; Cheung, Mitchell; Xu, Jinfei et al. (2016) Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations. Cancer Res 76:2836-44
Ohar, Jill A; Cheung, Mitchell; Talarchek, Jacqueline et al. (2016) Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. Cancer Res 76:206-15
Mesaros, Clementina; Blair, Ian A (2016) Mass spectrometry-based approaches to targeted quantitative proteomics in cardiovascular disease. Clin Proteomics 13:20

Showing the most recent 10 out of 20 publications