Phytochemicals & Metabolism in Pancreatic Diseases/Pandol, Stephen

来自人口研究的证据表明，水果和蔬菜中的植物化学物质提供了一个 对癌症包括胰腺癌的保护作用。大多数癌症患者除了 传统的治疗方法也使用天然的非处方抗癌药物，其中大多数是植物来源的。 因此，从机理上理解植物化学物质的潜在益处将是非常重要的。 预防胰腺癌以及增加胰腺癌风险的疾病的重要性 (i.e.慢性胰腺炎），通过确定这些分子在食物中的靶向途径和有益作用 和营养补充剂。 我们最近已经证明，生长因子和细胞外基质蛋白激活 胰腺癌细胞中的促生存途径，通过它们激活产生 活性氧（ROS）。此外，我们已经确定胰腺星状细胞，即细胞 在慢性胰腺炎和胰腺促纤维化反应中， 腺癌也使用ROS的产生来介导具有生长因子刺激的增殖。 在初步数据中，我们表明，选定的植物化学物质（罗特勒，鞣花酸，恩贝林，番茄红素）的作用， 两者均减弱胰腺癌和星状细胞中ROS的产生并抑制它们的DMA合成。 为了开始调查这些分子抗增殖作用的机制，我们 认为ROS在这些增殖细胞中是必需的，因为它们调节细胞的增殖。 戊糖循环途径，这反过来又是生产核糖和脱氧核糖所必需的， 核酸的合成。我们提供了初步的代谢组学数据来支持这一假设。 本项目中的实验旨在测试罗特勒林、鞣花酸、恩贝林、 姜黄素和番茄红素对调节胰腺星状细胞增殖代谢表型的作用， 癌细胞;并进一步确定它们对ROS产生的抑制在调节 这个phenotype。我们将利用这些信息设计实验来测试植物化学物质的预防作用 和/或治疗涉及星状细胞增殖性疾病的外分泌胰腺的两种疾病， 癌细胞-慢性胰腺炎和胰腺癌使用实验动物模型。

Evidence from population studies suggests that phytochemicals in fruits and vegetables provide a protective effect against cancer including pancreatic cancer. The majority of cancer patients besides traditional treatments also use natural non-prescription cancer drugs, of which, most are of plant origin. Therefore, the mechanistic understanding of potential benefits of phytochemicals would be of great importance in prevention of pancreatic cancer as well as disorders that increase the risk of pancreatic cancer (i.e. chronic pancreatitis) by identifying target pathways and beneficial effects of these molecules in foods and nutritional supplements. We have recently demonstrated that both growth factors and extracellular matrix proteins activate prosurvival pathways in pancreatic cancer cells through their ability to activate systems that generate reactive oxygen species (ROS). Further, we have determined that the pancreatic stellate cell, the cell responsible for fibrosis and inflammation in chronic pancreatitis and the desmoplastic reaction of pancreatic adenocarcinoma, also uses the production of ROS to mediate proliferation with growth factor stimulation. In preliminary data we show that selected phytochemicals (rottlerin, ellagic acid, embelin, lycopene) act to both attenuate the production of ROS in pancreatic cancer and stellate cells and inhibit their DMA synthesis. To initiate investigations into the mechanisms underlying the antiproliferative effects of these molecules we considered the possibility that ROS are necessary in these proliferative cells because they regulate the pentose cycle pathways which, in turn, are necessary for the production of ribose and deoxyribose for the synthesis of nucleic acids. We provide preliminary metabolomic data to support this hypothesis. The experiments in this project are designed to test the effect of each of rottlerin, ellagic acid, embelin, curcumin and lycopene on regulating the proliferative metabolic phenotype of the pancreatic stellate and cancer cells; and further to determine the role that their inhibition of ROS production plays in regulation of this phenotype. We will use this information to design experiments to test the phytochemicals for prevention and/or treatment of the two disorders of the exocrine pancreas involving proliferative disorders of stellate and cancer cells-chronic pancreatitis and pancreatic cancer using experimental animal models.