Secoisolariciresinol Diglucoside (SDB) Protection in Radiation Pheumonopathy

开环异落叶松树脂醇二葡萄糖苷 (SDB) 对放射性肺病的保护作用

• 批准号: 8501743
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501743
• 关键词: A549; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biological Assay; Cell Death; Cells; Cereals; Chemopreventive Agent; Chest; Clinic; Clinical Trials; Complex; Data; Development; Diet; Dietary Fiber; Dietary Formulations; Dietary Supplementation; Dose; Endothelial Cells; Ensure; Enzyme Gene; Enzymes; Epidermal Growth Factor Receptor; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Fibrosis; Flax; Free Radical Scavengers; Future; Generations; Genes; Goals; Growth; Human; In Vitro; Inflammation; Intestines; Ionizing radiation; K-ras mouse model; Knockout Mice; Lignans; Lung; Lung Neoplasms; Lung diseases; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Omega-3 Fatty Acids; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pneumonia; Property; Proto-Oncogene Proteins c-akt; Radiation; Radiation Injuries; Radiation Pneumonitis; Radiation Tolerance; Radiation Toxicity; Radiation therapy; Radioprotection; Radiosensitization; Reactive Oxygen Species; Reporter; Response Elements; Role; Signal Pathway; Specificity; Staging; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Effect; Thoracic Oncology; Time; Tissues; Toxic effect; Transcriptional Activation; Transgenic Organisms; angiogenesis; base; cancer cell; cancer radiation therapy; clinically significant; cytotoxic; design; enzyme therapy; flaxseed lignan; improved; in vivo; irradiation; killings; lung injury; mouse model; neoplastic cell; novel; novel therapeutics; protective effect; secoisolariciresinol diglucoside; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 胸腔放射疗法的有用性极大地受到对消除恶性细胞所需的辐射剂量的肺部敏感性的限制。多达30％因肺癌辐照的患者和其他约10-15％的其他胸部肿瘤学患者发生了临床上显着的辐射毒性。保护“正常”肺实质免受辐射损伤的需求损害了肿瘤放射疗法剂量的递送。因此，迫切需要增加放射疗法治疗比率的放射保护剂。电离辐射引起的活性氧物种对纤维化肺部疾病的发病机理显着贡献。然而，从氧化组织侮辱到晚期纤维化的分子途径尚不清楚，目前，没有自由基清除剂提供可接受的肺辐射保护水平，而没有严重的副作用。我们和其他人已经表明，抗氧化剂疗法减轻了辐射诱导的纤维化肺疾病，我们的初步数据表明，全graxsseed（FS）或FS Lignans，具有已知抗氧化剂，抗炎性，抗炎性和抗癌特性的生物活性化合物，诱导抗氧化型抗氧化剂，以启动性抗元素的抗性激活。此外，当在我们的胸椎辐射诱导的肺炎的小鼠模型中评估时，全谷物FS饮食可强大增加小鼠的存活，废除肺纤维化并减少氧化组织损伤，同时放射增强肺肿瘤。因此，我们假设饮食FS木质脂肪介导的抗氧化基因激活可能是减轻肺炎辐射肺炎的一种新型治疗策略。在当前的研究中，在AIM 1中，我们将使用Secoisoilariciresinol digucoside（SDG）的饮食中FS Lignan前体的饮食制剂探索FS Lignans的潜在肺辐射疗法的潜在肺部辐射肺损伤模型。在AIM 2中，我们将确定是否激活是否与保护机理有关，并确定其作用的细胞特异性。在AIM 3中，我们将使用新型的原位肺癌的K-RAS小鼠模型评估木质蛋白介导的肺癌细胞的放射敏化。成功完成拟议的研究将阐明该机制并确定FS木质介导的放射保护的有用性。目前，在全球临床试验中对可持续发展目标进行了评估，这一事实将有助于最终在肺癌放射疗法患者的诊所中测试该提案的发现。

项目成果

Radiation mitigating properties of the lignan component in flaxseed.

• DOI: 10.1186/1471-2407-13-179
• 发表时间: 2013-04-04
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Pietrofesa R;Turowski J;Tyagi S;Dukes F;Arguiri E;Busch TM;Gallagher-Colombo SM;Solomides CC;Cengel KA;Christofidou-Solomidou M
• 通讯作者: Christofidou-Solomidou M

Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel.

• DOI: 10.3390/ijms17060953
• 发表时间: 2016-06-16
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Pietrofesa RA;Velalopoulou A;Lehman SL;Arguiri E;Solomides P;Koch CJ;Mishra OP;Koumenis C;Goodwin TJ;Christofidou-Solomidou M
• 通讯作者: Christofidou-Solomidou M

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage.

合成开环异落叶松树脂醇二葡萄糖苷 (LGM2605) 在质子辐射损伤的离体模型中保护人肺。

• DOI: 10.3390/ijms18122525
• 发表时间: 2017
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Velalopoulou,Anastasia;Chatterjee,Shampa;Pietrofesa,RalphA;Koziol-White,Cynthia;Panettieri,ReynoldA;Lin,Liyong;Tuttle,Stephen;Berman,Abigail;Koumenis,Constantinos;Christofidou-Solomidou,Melpo
• 通讯作者: Christofidou-Solomidou,Melpo

Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation.

接受放化疗的非小细胞肺癌患者的膳食亚麻籽。

• DOI: 10.4172/2161-105x.1000154
• 发表时间: 2013
• 期刊: Journal of pulmonary & respiratory medicine
• 作者: Berman,AbigailT;Turowski,Jason;Mick,Rosemarie;Cengel,Keith;Farnese,Nicole;Basel-Brown,Lisa;Mesaros,Clementina;Blair,Ian;Lawson,James;Christofidou-Solomidou,Melpo;Lee,James;Rengan,Ramesh
• 通讯作者: Rengan,Ramesh

Applications of Out of Body Lung Perfusion.

体外肺灌注的应用。

• DOI: 10.1016/j.acra.2018.05.022
• 发表时间: 2019
• 期刊: Academic radiology
• 影响因子: 4.8
• 作者: Zhu,Bing;Suzuki,Yoshikazu;DiSanto,Thomas;Rubin,Samantha;Penfil,Zachary;Pietrofesa,RalphA;Chatterjee,Shampa;Christofidou-Solomidou,Melpo;Cantu,Edward
• 通讯作者: Cantu,Edward