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）：膀胱癌代表着重大的公共卫生负担。从诊断到死亡的每名膀胱癌患者的费用是所有癌症中最高的（在美国，每位患者$ 96,000至187美元，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，并且植物来源食品中包含的许多潜在保护性化合物集中在尿液中，因此植物中的生物活性剂可能在膀胱癌化学预防中起作用。 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说，尽管南太平洋岛屿人口中有许多吸烟者存在许多吸烟者，但高卡瓦消费量与较低的癌症发生率相关。 2）体外细胞培养研究表明，Kava提取物中的黄牛蛋白酶而不是卡瓦乳酮对人膀胱癌细胞的抗增殖和凋亡作用很强，其特征为低等级。 3）浅表和侵入性膀胱癌的异种移植模型中的抑制肿瘤生长，没有任何明显的副作用； 4）类似于其他一些Chalcone类似的Flavokawain A的化学结构使我们预测它不会直接损害DNA，与β-微管蛋白结合并诱导II期酶以预防致癌作用。我们假设Flavokawain A通过增强细胞周期调节并提高凋亡机制的敏感性对膀胱上皮具有化学预防作用。三种小鼠模型将用于检验这一假设：一种致癌物[4-羟基丁基（丁基）硝酸（OH-BBN）] - 小鼠膀胱中诱导的致癌模型，两个自发的小鼠膀胱转基因癌变模型，每个都将解决不同的问题。小鼠中的OH-BBN模型将用于检查Flavokawain A在初级预防方面的效用；为了防止在诸如吸烟和工业暴露等危险因素的人中首次发生膀胱癌。转基因模型各自引起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所见。在这些转基因模型中检查Flavokawain A将提供有关其在二级预防中有用的信息，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，PLK1，14-3-3-3-GAMMA和SKP-2），用于诱发细胞凋亡和细胞周期停滞时，用于黄酮。我们将通过在这些测试的动物模型中检查其体内表达，并使用RNA干扰和过表达矢量来确定它们对Flavokawain A在体外的作用以及研究这些目标的下游事件来验证这些靶标。这些研究将共同对黄合蛋白A作为化学剂和/或化学治疗剂的承诺提供坚定的答案。项目叙述性尽管膀胱癌是化学预防的理想候选者，但当前可用的化学预防剂数量有限。 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原位。 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.