Kava extract, Flavokawains and Bladder Cancer Prevention

描述(由申请人提供) 膀胱癌仍然是一个主要的公共卫生负担。在南太平洋群岛，卡瓦作为一种饮料、药物和社会宗教活动有着悠久的历史，类似于西方对葡萄酒的使用。在斐济、瓦图和西萨摩亚等饮用卡瓦的国家，消费几个世纪以来没有重大副作用的传统卡瓦制剂与较低和不寻常的性别比(女性癌症比男性多)和癌症发病率相关。我们最近鉴定了一种卡瓦提取物和三种查尔酮提取物是诱导膀胱癌细胞凋亡的物质。此外，我们还发现，查尔酮的主要成分黄酮胺A的细胞凋亡作用与其诱导线粒体凋亡通路和抑制核因子-kappaB介导的抗凋亡通路有关。由于研究表明，细胞凋亡途径的频繁改变导致细胞凋亡抵抗可能是膀胱癌发生的必备因素，因此，可以诱导细胞凋亡和抑制抗细胞凋亡信号的药物值得在膀胱癌预防中研究。我们推测，含有黄酮苷A的卡瓦提取物具有抗肿瘤和化学预防膀胱癌的活性，其机制是通过强有力地诱导癌前细胞和恶性细胞的凋亡。我们的具体目标有两个方面。首先，我们将确定卡瓦提取物和黄瓜A对裸鼠膀胱癌移植瘤形成和生长的抑制作用，以及黄瓜A对卡瓦提取物作用的需求。其次，我们将确定和比较黄酮苷A和卡瓦提取物对正常、癌前和恶性膀胱癌细胞的凋亡和抗凋亡信号的作用机制。从这些研究中获得的知识应该使我们能够1)设计出更好的Kava产品，使其具有优化的黄酮胺A和Kavalactone的比例，用于膀胱癌预防的翻译研究；2)设计更好的流行病学研究，以调查Kava产品或Kava产品的使用与膀胱癌风险，特别是与一般健康影响的关系。

DESCRIPTION (provided by applicant) Bladder cancer remains a major public health burden. Kava has a long history of serving as a beverage, medicine and in socio-religious functions in the South Pacific Islands, similar to the Western use of wine. Consumption of traditional aqueous kava preparation without major side effects for centuries correlates with lower and uncustomary sex ratio (more cancer in women than men) of, cancer incidences in kava-drinking countries such as Fiji, Vatu and Western Samoa. We recently have identified a kava extract and three chalcones from the extract as inducers of apoptosis in bladder cancer cells. Furthermore, we found that the apoptotic effect of flavokawain A, a major chalcone, was associated with the induction of the mitochondrial apoptotic pathway and inhibition of NF-kappa B mediated anti-apoptotic pathway. Since studies suggest that frequent alterations in apoptotic pathways leading to resistance of apoptosis may be obligatory for bladder carcinogenesis, agents that can induce apoptotic and inhibit anti-apoptotic signaling deserve study in bladder cancer prevention. We hypothesize that kava extracts that contain flavokawain A have antineoplastic and chemopreventive activities against bladder cancer via a robust induction of apoptosis in pre-malignant and malignant cells. Our specific aims are two fold. First, we will determine the ability of kava extracts and flavokwain A to reduce tumor formation and growth of the transplanted bladder cancer cells in nude mice, and the requirement of flavokawain A for kava extracts' effect. Second, we will define and compare the mechanisms of flavokawain A and kava extracts' actions on apoptotic and anti-apoptotic signaling in normal, pre-malignant and malignant bladder cancer cells. The knowledge generated from these studies should allow us to 1) devise better kava product with optimized ratio of flavokawain A and kavalactones for translation research in bladder cancer prevention; 2) design better epidemiological study to investigate the relationship between use of kava products or kava and risk of bladder cancer in particular and health effects in general.