New Mechanisms of Anti-tumor Activity of A-type PACs from Cranberries

蔓越莓 A 型 PAC 抗肿瘤活性新机制

• 批准号: 8775627
• 负责人: Laura Marie Bystrom
• 金额: $ 6.65万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775627
• 关键词: Affect; Aftercare; Anemia; Anemia due to Chronic Disorder; Animals; Apoptosis; Biological Assay; Biological Markers; Breast Cancer Cell; Cancer cell line; Cell Death; Cell Differentiation process; Cell Line; Cells; Chelating Agents; Chemicals; Chronic Disease; Complementary Medicine; Cranberries; DNA biosynthesis; Diet; Disease; Effectiveness; Enterocytes; Erythrocytes; Ethers; Exhibits; Flow Cytometry; Gene Expression; Gene Expression Profiling; Goals; Growth; Harvest; Hematology; Hepatocyte; Human; Immunohistochemistry; Implant; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 alpha; Interleukin-6; Iron; Iron Chelating Agents; Life; Lipopolysaccharides; Longevity; Malignant Neoplasms; Medical Research; Melanoma Cell; Metabolism; Methods; Modeling; Mus; Normal Cell; Pathway interactions; Patients; Play; Preparation; Proanthocyanidins; Process; Production; Property; Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Research; Research Project Grants; Research Training; Role; Source; Specificity; Structure; Testing; Therapeutic; Transferrin; Transferrin Receptor; Work; absorption; base; cancer cell; cancer prevention; cancer stem cell; cancer therapy; carcinogenesis; cytokine; dimer; hepcidin; in vivo; inflammatory marker; interest; iron metabolism; leukemia; macrophage; melanoma; metal transporting protein 1; neoplastic cell; oncology; overexpression; prevent; rapid growth; skills; suicide gene; tumor; tumor growth; tumor metabolism; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): There has been limited effort to study the role of iron in association with inflammation and treatment or prevention of cancer, especially from dietary sources or complementary medicines. A unique class of compounds from cranberries, known as A-type proanthocyanidins (A-PACs), have iron chelating properties and are the major component of cranberry fractions that have exhibited anti-tumor effects against several human cancer cell lines. Cranberry A-PAC fractions have also inhibited the inflammatory mediator Interleukin(IL)-6, a cytokine that affects iron metabolism and contributes to anemia of inflammation from chronic disease. The proposed research project will investigate the anti-tumor activities of A-PACs and their effects on anemia in relation to inflammation, and iron metabolism. The iron biomarkers, hepcidin, ferroportin, transferrin receptor and the inflammatory cytokines, IL-1alpha and IL-6 are of particular interest for this project. The anti-tumor activity of A-PACs will be tested at three different levels in vitro and in vivo with melanoma and leukemia cell lines. Tumor cells and mice implanted with tumors, will be treated with 1) a cranberry supplement with high A-PAC content 2) an A-PAC mixture consisting of mostly A-PAC dimers/trimers; 3) an A-PAC dimer or trimer. Iron metabolism and inflammation markers will be evaluated by qPCR, immunohistochemistry or other methods after treatment with A-PACs. An anemia of inflammation model recently developed by our lab will prolong the life of mice with tumors by an inducible suicide gene and provide systemic effects more similar to humans. Several hematological parameters, iron, and inflammation biomarkers will be analyzed in this model with and without the treatment of A-PACs. In addition, structural studies of A-PACs and their anti-tumor effects will be conducted in vitro by comparison of an A-PAC dimer with a similar compound lacking the ether bond. Changes in reactive oxygen species (ROS) and prosurvival factors of tumor cells treated with A-PACs in vitro will also be assessed to better understand the pathways involved in anti-tumor activity. Results from this research will provide more information about the mechanisms of A- PACs in relation to anti-tumor activities, altered iron metabolism and anemia of inflammation. These studies will also provide medical research training in hematology/oncology and further characterize the association of cancer with iron metabolism and inflammatory states.

描述(由申请人提供)：研究铁在炎症和癌症治疗或预防中的作用的努力有限，特别是从饮食来源或补充药物方面。小红莓中的一种独特的化合物，被称为A型原花青素(A-PAC)，具有铁络合特性，是小红莓提取物的主要成分，已显示出对几种人类癌细胞株的抗肿瘤作用。蔓越莓A-PAC组分还抑制了炎症介质白介素6(IL)-6，这是一种影响铁代谢的细胞因子，有助于慢性疾病引起的炎症贫血。这项拟议的研究项目将调查A-PAC的抗肿瘤活性及其对与炎症和铁代谢有关的贫血的影响。铁生物标志物，海普西丁，铁蛋白，转铁蛋白受体和炎性细胞因子，IL-1α和IL-6是这个项目特别感兴趣的。A-PACs的抗肿瘤活性将在三个不同的水平上进行体外和体内黑色素瘤和白血病细胞株的测试。对于肿瘤细胞和植入肿瘤的小鼠，将使用1)高A-PAC含量的小红莓补充剂进行治疗；2)主要由A-PAC二聚体/三聚体组成的A-PAC混合物；3)A-PAC二聚体或三聚体。铁代谢和炎症标志物将在A-PAC治疗后通过定量聚合酶链式反应、免疫组织化学等方法进行评估。我们实验室最近建立的炎性贫血模型将通过可诱导的自杀基因延长荷瘤小鼠的生命，并提供与人类更相似的全身效应。在这个模型中，在A-PAC治疗和不治疗的情况下，将分析几个血液学参数、铁和炎症生物标志物。此外，将通过比较A-PAC二聚体和类似的缺少醚键的化合物来研究A-PAC的结构及其体外抗肿瘤作用。此外，还将评估A-PAC体外处理的肿瘤细胞中活性氧簇(ROS)和生存因子的变化，以更好地了解参与抗肿瘤活性的途径。这项研究的结果将提供更多关于A-PAC与抗肿瘤活性、铁代谢改变和炎症贫血有关的机制的信息。这些研究还将提供血液学/肿瘤学方面的医学研究培训，并进一步确定癌症与铁代谢和炎症状态的关系。