Chemoprevention of urinary bladder carcinogenesis by flavokawain A

黄素卡因 A 对膀胱癌的化学预防

• 批准号: 8209757
• 负责人: Xiaolin Zi
• 金额: $ 8.61万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209757
• 关键词: Address; Adverse effects; Affect; Age; Animal Model; Apoptosis; Apoptotic; Area; BAX gene; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; BIRC4 gene; Binding; Bladder; Bladder Neoplasm; Body Weight; CYP1B1 gene; Cancer Patient; Carcinogens; Carcinoma in Situ; Cdc25C protein; Cell Culture Techniques; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Cell Line; Cells; Cessation of life; Chalcone; Chalcones; Chemical Structure; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Consumption; DNA; DNA Binding; Data; Development; Diagnosis; Diet; Disease; Down-Regulation; Enzymes; Epidemiologic Studies; Epithelial Cells; Epithelium; Event; Exhibits; Exposure to; Family; Family member; Food; Frequencies; Goals; High Prevalence; Human; Immunohistochemistry; Immunoprecipitation; In Vitro; Incidence; Induction of Apoptosis; Kava; MCL1 gene; MDM2 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metabolism; Methods; Microarray Analysis; Mitochondria; Modeling; Molecular; Morphology; Mus; Nature; New Agents; Nitrosamines; Normal Cell; Pacific Islands; Papillary; Papillary Carcinoma; Papillary Neoplasm; Papillary Transitional Cell Carcinoma; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Pilot Projects; Plant Roots; Plants; Play; Population; Post-Translational Protein Processing; Premalignant; Primary Prevention; Principal Investigator; Prodrugs; Proteins; Public Health; RNA Interference; Recurrence; Reporting; Risk Factors; Role; S Phase; SKP2 gene; Secondary Prevention; Smoker; Solid; Staging; Stream; Testing; Time; Tobacco smoking; Toxic effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; Transitional Cell Carcinoma; Tumor Burden; Tumor Weights; Up-Regulation; Ureter; Urine; Urothelium; Weight; Western Blotting; Xenograft Model; base; beta Tubulin; bladder cancer prevention; cancer cell; cancer chemoprevention; cancer recurrence; carcinogenesis; chemotherapeutic agent; cigarette smoking; cost; cyclin-dependent kinase inhibitor 1B; dietary supplements; feeding; human PLK1 protein; in vivo; indexing; innovation; interest; kavain; knock-down; mouse model; mutant; novel; oncoprotein p21; overexpression; prevent; programs; survivin; tumor; tumor growth; tumor progression; vector

Project Summary Bladder cancer represents a major public health burden. The cost per bladder cancer patient from diagnosis to death is the highest among all cancers ($96,000 to $187, 000 per patient in the US). Our long-term goal is to develop new chemopreventive agents to reduce the burden of bladder cancer. Because exposure to carcinogens is the major risk factor for bladder cancer and many potentially protective compounds contained in plant-derived food are concentrated in the urine, it is plausible that bioactive agents in plants may play a role in bladder cancer chemoprevention. Flavokawain A is the predominant chalcone identified from kava root extract. The promise of flavokawain A is based on the following data : 1) an epidemiological study reported that high kava consumption correlated with lower incidences of cancers despite the presence of many smokers in the populations of the South Pacific Islands; 2) In vitro cell culture studies showed that flavokawains but not kavalactones in kava extracts exhibited strong antiproliferative and apoptotic effects on human bladder cancer cells characterized as low- and high- grades; 3) Flavokawain A inhibited tumor growth in xenograft models of superficial and invasive bladder cancer without any noticeable side effects; and 4) The chemical structure of flavokawain A, similar to some other chalcones, leads us to predict that it would cause no direct damage to DNA, bind to beta-tubulin, and induce phase II enzymes to protect against carcinogenesis. We hypothesize flavokawain A has chemopreventive effects on bladder epithelium via enhancing cell cycle regulation and increasing the sensitivity of apoptotic mechanisms. Three mouse models will be used to test this hypothesis: a carcinogen [4-hydroxybutyl (butyl) nitrosamine (OH-BBN)]-induced carcinogenesis model in mice bladders, and two spontaneous mouse bladder transgenic carcinogenesis models, each of which will address distinct issues. The OH-BBN model in mice will be used to examine flavokawain A's utility in primary prevention; for preventing the first occurrence of bladder cancer in those with risk factors such as cigarette smoking and industrial exposures. The transgenic models each induce a separate precursor state to advanced bladder cancer: either papillary tumors or carcinoma in situ, as seen in early stages of clinical bladder cancer. Examining flavokawain A in these transgenic models will provide information about its usefulness in secondary prevention, which clinically will address preventing bladder cancer recurrence and progression. Our microarray analysis has identified a few potential transcriptional targets (i.e. BIM, BID, survivin, Plk1, 14-3-3gamma, and SKP-2) for flavokawain A when inducing apoptosis and cell cycle arrests. We will validate these targets by examining their expression in vivo in these tested animal models and by using RNA interference and overexpression vectors to determine their contributions to flavokawain A's action in vitro, as well as by studying the down-stream events of these targets. Together, these studies will provide a firm answer to the promise of flavokawin A as a chemoprventative and/or chemotherapeutic agent.

项目摘要 膀胱癌是一个主要的公共卫生负担。每名膀胱癌患者从诊断到 在所有癌症中死亡率最高（在美国每个病人96，000到187，000美元）。我们的长期目标是 开发新的化学预防剂，以减少膀胱癌的负担。因为暴露在 致癌物是膀胱癌的主要危险因素， 植物源性食物集中在尿液中，植物中的生物活性剂可能在尿液中发挥作用，这是合理的。 膀胱癌的化学预防卡瓦黄素A是从卡瓦根提取物中鉴定的主要查耳酮。 flavokawain A的承诺是基于以下数据：1）流行病学研究报告， 卡瓦消费与较低的癌症发病率相关，尽管存在许多吸烟者， 2）体外细胞培养研究表明，flavokawain，但不是 卡瓦提取物中的卡瓦内酯对人膀胱癌具有较强的抗增殖和凋亡作用 细胞的特征为低和高级别; 3）在异种移植模型中，卡瓦胡椒素A抑制肿瘤生长。 浅表性和浸润性膀胱癌，没有任何明显的副作用;以及4） flavokawain A，类似于其他一些查耳酮，使我们预测，它不会造成直接损害， DNA，结合β-微管蛋白，并诱导II相酶，以防止致癌。我们假设 卡瓦胡椒素A通过促进细胞周期调节对膀胱上皮细胞具有化学预防作用 并增加凋亡机制的敏感性。将使用三个小鼠模型来测试这一点 一种致癌物[4-羟丁基（丁基）亚硝胺（OH-BBN）]诱导小鼠致癌模型 膀胱，和两个自发的小鼠膀胱转基因致癌模型，每一个都将解决 不同的问题。小鼠中的OH-BBN模型将用于检查黄素卡瓦菌素A在原发性肿瘤中的效用。 预防;用于预防有危险因素（如吸烟）的人首次发生膀胱癌 吸烟和工业暴露。每个转基因模型诱导一个单独的前体状态， 膀胱癌：乳头状肿瘤或原位癌，见于临床膀胱癌的早期阶段。 在这些转基因模型中检查黄素卡瓦文A将提供关于其在中学中的有用性的信息。 预防，这将在临床上解决预防膀胱癌复发和进展。我们的微阵列 分析已经确定了一些潜在的转录靶点（即BIM、BID、生存素、Plk 1、14-3- 3 γ和 SKP-2）在诱导细胞凋亡和细胞周期停滞时对卡瓦胡椒素A的作用。我们将通过以下方式验证这些目标： 在这些测试的动物模型中并通过使用RNA干扰检测它们的体内表达， 过表达载体，以确定它们对黄素卡瓦菌素A的体外作用的贡献，以及通过研究 这些目标的下游事件。总之，这些研究将提供一个坚定的答案， 作为化学预防剂和/或化学治疗剂的黄酮卡霉素A。