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：
7538351
负责人：
Xiaolin Zi
金额：
$ 31.93万
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/7538351
关键词：
Address Adverse effects Affect Age Animal Model Apoptosis Apoptotic Area Aromatic Amines BAX gene BCL2 gene BCL2L11 gene BIRC4 gene Binding Bladder Bladder Neoplasm Body Weight Breast Cancer Prevention CYP1B1 gene Cancer Patient Carcinogens Carcinoma in Situ 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 Treatment Clinical Trials Consumption DNA DNA Binding Data Development Diagnosis Diet Disease Down-Regulation Enzymes Epidemiologic Studies Epithelial Cells Epithelium Event Excision Exhibits Exposure to Family Family member Food Frequencies Goals Hereditary Breast Carcinoma High Prevalence Human Immunohistochemistry Immunoprecipitation In Vitro Incidence Induction of Apoptosis Infiltration Kava MCL1 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Metabolism Methods Microarray Analysis Mitochondria Modeling Molecular Morphology Mus Muscle Nature New Agents Nitrosamines Normal Cell Occupational Exposure Pacific Islands Papillary Papillary Neoplasm Papillary Transitional Cell Carcinoma Pathway interactions Patients Phase Phosphorylation Phosphotransferases Pilot Projects Plant Roots Plants Play Population Post-Translational Protein Processing Premalignant Prevalence Preventive Primary Prevention Prodrugs Proteins Protocols documentation Public Health RNA Interference Radiation Radical Cystectomy Recurrence Refractory Reporting Risk Factors Role SKP2 gene Secondary Prevention Smoke Smoker Smoking History Solid Staging Stream Survival Rate TP53 gene Testing Time Tobacco Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms Transitional Cell Carcinoma Transurethral Resection 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 chemotherapy cigarette smoking cost cyclin-dependent kinase inhibitor 1B dietary supplements feeding human PLK1 protein human old age (65+)improved in vivo indexing innovation interest intravesical kavain knock-down modifiable risk mouse model mutant novel novel strategies older patient oncoprotein p21 overexpression prevent smoking cessation survivin tumor tumor growth tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): 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.Project Narrative Although bladder cancer is an ideal candidate for chemoprevention, the number of currently available chemopreventive agents is limited. We will examine the chemopreventive activities of a novel agent, flavokawain A, in a carcinogen [4-hydroxybutyl (butyl) nitrosamine (OH-BBN)]-induced mouse bladder carcinogenesis model, and two novel bladder transgenic mouse models each which induces a separate precursor state to advanced bladder cancer: either papillary transitional cell carcinoma or carcinoma in situ. In addition, we will validate potential transcriptional targets (i.e., BIM, BID, survivin, Plk1, 14-3-3gamma, and SKP-2) for flavokawain A-induced apoptosis and cell cycle arrests 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.

描述（由申请人提供）：膀胱癌是一项重大的公共卫生负担。每个膀胱癌患者从诊断到死亡的费用是所有癌症中最高的（美国每个患者为 96,000 美元至 187, 000 美元）。我们的长期目标是开发新的化学预防药物以减轻膀胱癌的负担。由于接触致癌物质是膀胱癌的主要危险因素，并且植物源性食品中含有的许多潜在保护性化合物浓缩在尿液中，因此植物中的生物活性剂可能在膀胱癌化学预防中发挥作用，这是合理的。 Flavokawain A 是从卡瓦根提取物中鉴定出的主要查尔酮。黄卡瓦素 A 的前景基于以下数据：1) 一项流行病学研究报告称，尽管南太平洋岛屿人口中存在许多吸烟者，但高卡瓦消费量与较低的癌症发病率相关； 2) 体外细胞培养研究表明，卡瓦提取物中的黄酮卡因而非卡瓦内酯对人低级别和高级膀胱癌细胞表现出强烈的抗增殖和凋亡作用； 3) Flavokawain A 抑制浅表性膀胱癌和浸润性膀胱癌异种移植模型中的肿瘤生长，且没有任何明显的副作用； 4) 黄卡因 A 的化学结构与其他一些查耳酮类似，使我们预测它不会对 DNA 造成直接损伤，与 β-微管蛋白结合，并诱导 II 相酶来防止癌变。我们假设黄卡因 A 通过增强细胞周期调节和增加细胞凋亡机制的敏感性对膀胱上皮具有化学预防作用。将使用三种小鼠模型来检验这一假设：一种致癌物[4-羟丁基（丁基）亚硝胺（OH-BBN）]诱导的小鼠膀胱癌发生模型，以及两种自发性小鼠膀胱转基因癌变模型，每种模型都将解决不同的问题问题。小鼠 OH-BBN 模型将用于检验黄素卡因 A 在一级预防中的效用；用于预防有吸烟和工业接触等危险因素的人首次患上膀胱癌。转基因模型各自诱导晚期膀胱癌的单独前体状态：乳头状肿瘤或原位癌，如临床膀胱癌的早期阶段所见。在这些转基因模型中检查黄素卡因 A 将提供有关其在二级预防中的有用性的信息，这在临床上将解决预防膀胱癌复发和进展的问题。我们的微阵列分析确定了黄素卡因 A 在诱导细胞凋亡和细胞周期停滞时的一些潜在转录靶点（即 BIM、BID、生存素、Plk1、14-3-3gamma 和 SKP-2）。我们将通过检查这些靶标在这些测试动物模型中的体内表达、使用 RNA 干扰和过表达载体来确定它们对黄素卡因 A 体外作用的贡献以及研究这些靶标的下游事件来验证这些靶标。总之，这些研究将为 flavokawin A 作为化学预防剂和/或化疗剂的前景提供坚定的答案。项目叙述尽管膀胱癌是化学预防的理想候选者，但目前可用的化学预防剂的数量有限。我们将研究一种新型药物黄卡因 A 在致癌物 [4-羟丁基（丁基）亚硝胺 (OH-BBN)] 诱导的小鼠膀胱癌模型中的化学预防活性，以及两种新型膀胱转基因小鼠模型，每种模型均诱导单独的膀胱癌晚期膀胱癌的前兆状态：乳头状移行细胞癌或原位癌。此外，我们将通过检查这些测试的体内表达来验证黄素卡因 A 诱导的细胞凋亡和细胞周期停滞的潜在转录靶点（即 BIM、BID、生存素、Plk1、14-3-3gamma 和 SKP-2）。动物模型，并通过使用 RNA 干扰和过表达载体来确定它们对黄素卡因 A 体外作用的贡献。