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。卡瓦在南太平洋岛屿作为饮料、药物和社会宗教功能方面有着悠久的历史，类似于西方对葡萄酒的使用。 几个世纪以来，传统的卡瓦水制剂的消费没有重大副作用，这与斐济、瓦图和西萨摩亚等卡瓦饮用国癌症发病率的较低和非常规性别比例（女性癌症多于男性）有关。我们最近已经确定了卡瓦提取物和三个查尔酮提取物作为诱导膀胱癌细胞凋亡。此外，我们发现，黄酮卡瓦因A，一个主要的查耳酮，凋亡作用与诱导线粒体凋亡途径和抑制NF-κ B B介导的抗凋亡途径。由于研究表明，导致细胞凋亡抵抗的细胞凋亡途径的频繁改变可能是膀胱癌发生的必要条件，因此，可以诱导细胞凋亡并抑制抗细胞凋亡信号传导的药物值得在膀胱癌预防中进行研究。我们假设，卡瓦提取物，含有黄素卡瓦A通过一个强大的诱导细胞凋亡的癌前和恶性细胞对膀胱癌的肿瘤和化学预防活动。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素卡瓦素A减少裸鼠移植膀胱癌细胞的肿瘤形成和生长的能力，以及卡瓦提取物作用对黄素卡瓦素A的需求。其次，我们将定义和比较卡瓦胡椒素A和卡瓦提取物在正常、癌前和恶性膀胱癌细胞中对凋亡和抗凋亡信号传导的作用机制。从这些研究中产生的知识应该使我们能够：1）设计出更好的卡瓦产品，其中具有优化的卡瓦黄素A和卡瓦内酯比例，用于膀胱癌预防的翻译研究; 2）设计更好的流行病学研究，以调查卡瓦产品或卡瓦的使用与膀胱癌风险之间的关系，特别是对健康的影响。

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.