Polyphenols Regulate Lipid Inflamm Processes in Pancreatic Cancer/Harris, Diane

胰腺导管腺癌(Pda)是美国癌症相关死亡的第四大原因。 各州。在诊断时，大多数患者都有转移性疾病，尽管试图使用 独特的联合治疗，5年存活率仍为4%。尽管已经取得了重要进展 在对其生物学的了解中，这一知识尚未导致患者存活率的实质性变化。 显然，有必要为PDA的治疗制定新的更好的策略。炎症性 过程有助于癌症的发生和癌症的进展。二十烷类化合物，由 环氧合酶和脂氧合酶活性是炎症性和非炎症性疾病中产生的重要生物活性脂质。 肿瘤的情况。抑制二十烷类化合物的产生减少了发病率并减少了 人类癌症的进展。来自食物来源和膳食补充剂的多酚化合物 已被证明通过抑制环氧合酶和/或脂氧合酶具有抗炎特性 活动。根据我们初步的数据和现有的文献，我们假设多酚 绿茶和黄芩中的化合物：1)抑制细胞增殖和二十烷类化合物的产生 在PDA细胞中；2)降低发生PDA的风险(预防效果)；以及，3)减少生长和扩散 已建立的PDA(治疗效果)。我们将研究绿茶(多酚E)和SB的作用机理 多酚在体外对细胞增殖、凋亡和细胞周期调节的作用以及稳定的同位素 动态代谢谱(SIDMAP)技术评价阿司匹林的整体表型效应 PDA细胞上的多酚类物质。此外，我们将使用老鼠模型来确定多酚E和SB是否在 在PDA转基因模型(预防模型)中抑制胰腺癌的发生并减少PDA细胞 异种原位移植模型(治疗模型)中的生长。我们建议的一个独特方面是使用稳定的 以同位素为基础的代谢组学方法研究人体不同阶段代谢通量的变化 转基因小鼠的致癌过程。我们的发现将形成未来饮食的理论基础 涉及植物营养素的建议，并为开发临床试验提供科学背景 旨在评估多酚化合物的潜在治疗和预防益处 PDA中的绿茶、SB和其他植物性物质。

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States. At the time of diagnosis most patients have metastatic disease and despite attempts to employ unique combination therapies the 5-year survival remains 4%. Although important progress has been made in understanding its biology, this knowledge has not yet resulted in a substantial change in patient survival and there is clearly a need to develop new and better strategies for the treatment of PDA. Inflammatory processes are instrumental to carcinogenesis and cancer progression. Eicosanoids, formed by cyclooxygenase and lipoxygenase activity, are important bioactive lipids produced in inflammatory and neoplastic conditions. Inhibition of eicosanoid production reduces the incidence and diminishes the progression of human cancers. Polyphenolic compounds from food sources and dietary supplements have been shown to possess anti-inflammatory properties via inhibition of cyclooxygenase and/or lipoxygenase activity. Based on data from our preliminary and the available literature, we hypothesize that polyphenolic compounds from green tea and Scutellaria baicalensis (SB): 1) inhibit proliferation and eicosanoid production in PDA cells; 2) lower the risk of developing PDA (preventive effect); and, 3) reduce the growth and spread of established PDA (therapeutic effect). We will study mechanisms of green tea (polyphenon E) and SB polyphenol action on proliferation, apoptosis, and cell cycle regulation in vitro as well as using stable isotopebased dynamic metabolic profiling (SIDMAP) technology to evaluate the overall phenotypic effect of polyphenols on PDA cells. In addition we will use mouse models to determine if polyphenon E and SB on can inhibit pancreatic carcinogenesis in a transgenic model of PDA (prevention model) and reduce PDA cell growth in the orthotopic xenograft model (treatment model). A unique aspect of our proposal is to use stable isotope-based metabolomics approach to relate changes in metabolic flux occuring at different stages in the carcinogenisis process in the transgenic mice. Our findings will form the rationale for future dietary recommendations involving phytonutrients and provide the scientific background for developing clinical trials designed to evaluate the potentially therapeutic and preventive benefit of polyphenolic compounds from green tea, SB, and other botanicals in PDA.