Usefulness of thoracic radiotherapy is greatly limited by lung sensitivity to irradiation doses necessary to eradicate malignant cells. Clinically significant radiation toxicity occurs in up to 30% of patients irradiated for lung cancer and about 10-15% of other thoracic oncology patients. The need to protect "normal" lung parenchyma from radiation injury compromises delivery of tumoricidal radiotherapy doses. Therefore, radioprotectors that would increase the therapeutic ratio of radiotherapy are urgently needed. Reactive oxygen species induced by ionizing radiation contribute significantly to the pathogenesis of fibrotic lung disease. However the molecular pathways from the oxidative tissue insult to late radiation fibrosis are unclear and at this time, no free radical scavenger offers acceptable levels of pulmonary radioprotection without serious side effects. We and others have shown that antioxidant enzyme therapy alleviates radiation- induced fibrotic lung disease and our preliminary data show that wholegrain flaxseed (FS) or FS lignans, bioactive compounds with known antioxidant, anti-inflammatory and anticarcinogenic properties, induce transcriptional activation of antioxidant enzyme genes in mouse lungs. Furthermore, when evaluated in our mouse model of thoracic radiation-induced pneumonopathy, whole grain FS diet robustly increased mouse survival, abrogated lung fibrosis and decreased oxidative tissue damage while radiosensitizing lung tumor. Therefore, we hypothesize that dietary FS lignan-mediated activation of antioxidant genes may be a novel therapeutic strategy to alleviate radiation pneumonopathy. In the current study, in Aim 1 we will explore the potential pulmonary radioprotective efficacy of FS lignans in a well-established murine model of radiation lung injury using dietary formulations of Secoisolariciresinol Diglucoside (SDG), the main FS lignan precursor.
In Aim 2 we will determine if ARE activation is implicated in the mechanism of protection and establish their cell specificity of action.
In Aim 3 we will evaluate lignan-mediated radiosensitization of lung cancer cells using a novel K-ras mouse model of orthotopic lung cancer. Successful completion of the proposed studies will elucidate the mechanism and determine the usefulness of FS lignan-mediated radioprotection. SDG is currently being evaluated in clinical trials worldwide a fact that will facilitate ultimately testing the findings of this proposal in the clinic on lung cancer radiotherapy patients.

Public Health Relevance

The usefulness of thoracic radiotherapy is limited by lung sensitivity to irradiation doses necessary to eradicate malignant cells. Therefore, the development of radioprotectors that would increase the therapeutic ratio of radiotherapy is urgently needed. Reactive oxygen species induced by ionizing radiation contribute significantly to the pathogenesis of fibrotic lung disease. We hypothesize that dietary FS lignans mediate the activation of antioxidant and cytoprotective genes as a novel therapeutic strategy to alleviate radiation pneumonopathy. In Aim 1 we'll explore the potential pulmonary radioprotective efficacy of FS lignans in a well-established murine model of radiation lung injury using dietary formulations Secoisolariciresinol Diglucoside (SDG), the main FS lignan precursor. In Aim 2 we will determine if Nrf2/ARE activation is implicated in the mechanism of their protection and establish cell specificity of their action. In Aim 3 we will evaluate lignan-mediated radiosensitization of lung cancer cells using a novel K-ras mouse model of orthotopic lung cancer. Successful completion of the proposed studies will elucidate the mechanism and determine the usefulness of FS lignan-mediated radioprotection enabling future clinical trials in the context of lung cancer radiotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133470-05
Application #
8307407
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Emenaker, Nancy J
Project Start
2008-09-26
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$317,009
Indirect Cost
$115,734
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua et al. (2016) Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice. J Biol Chem 291:8070-89
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; Arguiri, Evguenia et al. (2016) Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice. Carcinogenesis 37:177-87
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
Yabas, Mehmet; Elliott, Hannah; Hoyne, Gerard F (2015) The Role of Alternative Splicing in the Control of Immune Homeostasis and Cellular Differentiation. Int J Mol Sci 17:
Velalopoulou, Anastasia; Tyagi, Sonia; Pietrofesa, Ralph A et al. (2015) The Flaxseed-Derived Lignan Phenolic Secoisolariciresinol Diglucoside (SDG) Protects Non-Malignant Lung Cells from Radiation Damage. Int J Mol Sci 17:
Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia et al. (2015) Space radiation-associated lung injury in a murine model. Am J Physiol Lung Cell Mol Physiol 308:L416-28
Turowski, Jason B; Pietrofesa, Ralph A; Lawson, John A et al. (2015) Flaxseed modulates inflammatory and oxidative stress biomarkers in cystic fibrosis: a pilot study. BMC Complement Altern Med 15:148
Mishra, Om P; Pietrofesa, Ralph; Christofidou-Solomidou, Melpo (2014) Novel synthetic (S,S) and (R,R)-secoisolariciresinol diglucosides (SDGs) protect naked plasmid and genomic DNA From gamma radiation damage. Radiat Res 182:102-10
Christofidou-Solomidou, Melpo; Pietrofesa, Ralph; Arguiri, Evguenia et al. (2014) Dietary flaxseed modulates the miRNA profile in irradiated and non-irradiated murine lungs: a novel mechanism of tissue radioprotection by flaxseed. Cancer Biol Ther 15:930-7

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