Consumption of the traditional kava preparation was reported to correlate with low and uncustomary gender ratios (more
cancer in women than men) of
cancer incidences in three kava-drinking countries: Fiji, Vanuatu, and Western Samoa. We have identified
flavokawain A, B, and C but not the major kavalactone,
kawain, in kava extracts as causing strong antiproliferative and apoptotic effect in human
bladder cancer cells.
Flavokawain A results in a significant loss of mitochondrial membrane potential and release of
cytochrome c into the cytosol in an invasive
bladder cancer cell line T24. These effects of
flavokawain A are accompanied by a time-dependent decrease in Bcl-x(L), a decrease in the association of Bcl-x(L) to Bax, and an increase in the active form of
Bax protein. Using the primary mouse embryo fibroblasts Bax knockout and wild-type cells as well as a Bax inhibitor
peptide derived from the Bax-binding domain of Ku70, we showed that
Bax protein was, at least in part, required for the apoptotic effect of
flavokawain A. In addition,
flavokawain A down-regulates the expression of X-linked inhibitor of apoptosis and
survivin. Because both X-linked inhibitor of apoptosis and
survivin are main factors for apoptosis resistance and are overexpressed in
bladder tumors, our data suggest that
flavokawain A may have a dual efficacy in induction of apoptosis preferentially in
bladder tumors. Finally, the
anticarcinogenic effect of
flavokawain A was evident in its inhibitory growth of
bladder tumor cells in a nude mice model (57% of inhibition) and in soft
agar.