Kava extract, Flavokawains and Bladder Cancer Prevention

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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.