Chemoprevention of urinary bladder carcinogenesis by flavokawain A

黄素卡因 A 对膀胱癌的化学预防

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要膀胱癌代表着重大的公共卫生负担。从诊断到每个膀胱癌患者的费用死亡是所有癌症中最高的（在美国，每位患者的$ 96,000至$ 187，100 000）。我们的长期目标是开发新的化学预防剂，以减轻膀胱癌的负担。因为接触致癌物是膀胱癌的主要危险因素，也是许多潜在的保护性化合物植物来源的食物集中在尿液中，植物中的生物活性剂可能在膀胱癌化学预防。 Flavokawain A是从Kava根提取物中鉴定出的主要chalcone。 Flavokawain A的承诺基于以下数据：1）一项流行病学研究报告，高尽管许多吸烟者存在许多吸烟者南太平洋群岛的种群； 2）体外细胞培养研究表明，黄牛蛋白 Kava提取物中的Kavalactones对人膀胱癌表现出强烈的抗增生性和凋亡作用细胞以低等级为特征； 3）黄牛蛋白A的异种移植模型中的抑制肿瘤生长表面和侵入性膀胱癌没有任何明显的副作用； 4）化学结构类似于其他一些Chalcones类似的Flavokawain A导致我们预测它不会直接损害 DNA，与β-微管蛋白结合，并诱导II期酶预防癌变。我们假设 Flavokawain A通过增强细胞周期调节对膀胱上皮具有化学预防作用并提高凋亡机制的灵敏度。将使用三种鼠标模型来测试假设：一种致癌[4-羟基丁基（丁基）硝基胺（OH-BBN）] - 小鼠诱导的致癌模型膀胱和两个自发小鼠膀胱转基因癌变模型，每个模型都将解决不同的问题。小鼠中的OH-BBN模型将用于检查flavokawain A主要的效用预防;用于防止在诸如香烟等危险因素的人中首次发生膀胱癌吸烟和工业暴露。转基因模型每个模型都会引起单独的前体状态膀胱癌：正如临床膀胱癌的早期所见，乳头状肿瘤或原位癌。在这些转基因模型中检查Flavokawain A将提供有关其在次生中有用性的信息预防，在临床上将解决防止膀胱癌复发和进展。我们的微阵列分析已经确定了一些潜在的转录靶标（即BIM，BID，Survivin，PLK1，14-3-3-Gamma和 SKP-2）用于诱导细胞凋亡和细胞周期停滞时的黄牛a。我们将通过在这些测试的动物模型中检查它们在体内的表达以及使用RNA干扰和过表达向量以确定其对Flavokawain A在体外的作用的贡献，并通过研究这些目标的下游事件。这些研究将共同为承诺提供坚定的回答 Flavokawin A作为化学剂和/或化学治疗剂。