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).

Public Health Relevance

Occupational exposure to inhalation of airborne pollutants such as asbestos is linked to pulmonary inflammation, tissue fibrosis and cancer. Exposure to asbestos fibers has been linked to the development of malignant mesothelioma, however, the mechanism of cell damage and disease development is unclear. There is a critical need for non-toxic antioxidant and anti-inflammatory agents such as the flaxseed and its bioactive lignan SDG that we are proposing here, to prevent these processes that would ultimately lead to malignancy and fibrotic lung scaring.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1)
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Seifried, Harold E
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University of Pennsylvania
Internal Medicine/Medicine
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Mishra, Om P; Popov, Anatoliy V; Pietrofesa, Ralph A et al. (2018) Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits myeloperoxidase activity in inflammatory cells. Biochim Biophys Acta Gen Subj 1862:1364-1375
Pietrofesa, Ralph A; Chatterjee, Shampa; Park, Kyewon et al. (2018) Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos-Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner. Antioxidants (Basel) 7:
Mohanty, Sanjay K; Gonneau, Cedric; Salamatipour, Ashkan et al. (2018) Siderophore-mediated iron removal from chrysotile: Implications for asbestos toxicity reduction and bioremediation. J Hazard Mater 341:290-296
Pietrofesa, Ralph A; Woodruff, Patrick; Hwang, Wei-Ting et al. (2017) The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages. Oxid Med Cell Longev 2017:7395238
Velalopoulou, Anastasia; Chatterjee, Shampa; Pietrofesa, Ralph A et al. (2017) Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage. Int J Mol Sci 18:
Mishra, Om P; Popov, Anatoliy V; Pietrofesa, Ralph A et al. (2016) Gamma-irradiation produces active chlorine species (ACS) in physiological solutions: Secoisolariciresinol diglucoside (SDG) scavenges ACS - A novel mechanism of DNA radioprotection. Biochim Biophys Acta 1860:1884-97
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:
Pietrofesa, Ralph A; Velalopoulou, Anastasia; Albelda, Steven M et al. (2016) Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605). Int J Mol Sci 17:322
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
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

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