The usefulness of thoracic radiotherapy is greatly limited by the sensitivity of the lung tissue to irradiation doses necessary to eradicate malignant cells. Clinically significant radiation lung injury, such as pneumonia- like inflammation and late stage fibrosis, occurs in up to 30% of patients irradiated for lung cancer and about 10-15% of other thoracic oncology patients. The need, however, to protect """"""""normal"""""""" lung parenchyma from unacceptable radiation injury compromises the ability to deliver tumoricidal radiotherapy doses. Reactive oxygen species (ROS) such as those induced in large quantities by ionizing radiation are believed to 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, there is no available free radical scavenger to offer acceptable levels of pulmonary radioprotection without serious side effects. We and others have shown that antioxidant enzyme therapy alleviates radiation-induced fibrotic lung disease. The recently discovered NF-E2-related factor 2 (Nrf2), a key transcriptional regulator for antioxidant response element (ARE) mediates induction of cellular antioxidants and detoxifying proteins. We have preliminary data to support that curcumin and flaxseed lignans, safe, naturally occurring, plant-derived, pleiotropic compounds with known antioxidant, anti-inflammatory and anticarcinogenic characteristics, activate the Nrf2/ARE pathway and mediate transcription of antioxidant and cytoprotective genes. We hypothesize that coordinate induction of Nrf2/ARE regulated antioxidant genes may be a novel therapeutic strategy to alleviate radiation pneumonopathy. This study will determine using novel molecular methodologies, two potential mechanisms by which these agents activate Nrf2: kinase-mediated phosphorylation and increased Nrf2 protein stability (Specific Aim 1) and will explore the potential pulmonary radioprotective efficacy of these agents in a well-established murine model of radiation lung injury using dietary formulations of curcumin and flaxseed in Nrf2 trangenic animals and wild type controls (Specific Aim 2). The findings of this work regarding mechanism of action and their usefulness in lung radioprotection in experimental animals and the knowledge that these phytochemicals can be safely administered to humans will enable the design of future clinical trials in the context of cancer treatment. ? ?
| Lee, James C; Kinniry, Paul A; Arguiri, Evguenia et al. (2010) Dietary curcumin increases antioxidant defenses in lung, ameliorates radiation-induced pulmonary fibrosis, and improves survival in mice. Radiat Res 173:590-601 |
| Lee, James C; Krochak, Ryan; Blouin, Aaron et al. (2009) Dietary flaxseed prevents radiation-induced oxidative lung damage, inflammation and fibrosis in a mouse model of thoracic radiation injury. Cancer Biol Ther 8:47-53 |
| Lee, James C; Bhora, Faiz; Sun, Jing et al. (2008) Dietary flaxseed enhances antioxidant defenses and is protective in a mouse model of lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 294:L255-65 |
| Machtay, Mitchell; Scherpereel, Arnaud; Santiago, Jose et al. (2006) Systemic polyethylene glycol-modified (PEGylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the C57/bl6 mouse. Radiother Oncol 81:196-205 |
