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

描述（由申请人提供）：研究铁与炎症和治疗或预防癌症相关的作用的努力有限，特别是来自饮食来源或补充药物。蔓越莓中的一类独特化合物，称为A型原花青素（A-PAC），具有铁螯合特性，是蔓越莓组分的主要成分，对几种人类癌细胞系表现出抗肿瘤作用。蔓越莓A-PAC组分还抑制了炎症介质白细胞介素（IL）-6，这是一种影响铁代谢并导致慢性疾病炎症贫血的细胞因子。拟议的研究项目将研究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。铁生物标志物铁调素、铁转运蛋白、转铁蛋白受体和炎性细胞因子IL-1 α和IL-6是该项目特别感兴趣的。A-PAC的抗肿瘤活性将在体外和体内用黑素瘤和白血病细胞系在三个不同水平进行测试。肿瘤细胞和植入肿瘤的小鼠将用1）具有高A-PAC含量的蔓越莓补充剂2）主要由A-PAC二聚体/三聚体组成的A-PAC混合物; 3）A-PAC二聚体或三聚体治疗。A-PAC治疗后，将通过qPCR、免疫组织化学或其他方法评价铁代谢和炎症标志物。我们实验室最近开发的炎症贫血模型将通过诱导自杀基因延长肿瘤小鼠的寿命，并提供更类似于人类的全身效应。将在该模型中分析几个血液学参数、铁和炎症生物标志物，包括A-PAC治疗和未治疗。此外，A-PAC的结构研究及其抗肿瘤作用将通过比较A-PAC二聚体与缺乏醚键的类似化合物在体外进行。还将评估体外用A-PAC处理的肿瘤细胞的活性氧（ROS）和促生存因子的变化，以更好地了解参与抗肿瘤活性的途径。本研究的结果将为A-PAC的抗肿瘤作用、铁代谢改变和炎症性贫血的机制提供更多的信息。这些研究还将提供血液学/肿瘤学方面的医学研究培训，并进一步表征癌症与铁代谢和炎症状态的相关性。

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.