Flavonoids synthesized from chalcone precursors in plants have been shown to possess
cytotoxic activities with therapeutic potential. We have isolated the novel chalcone
flavokawain B from Alpinia pricei Hayata, a plant native to Taiwan that is used in
food and traditional Chinese medicine. Here, we report for the first time that flavokawain
B significantly inhibits the growth of colon cancer cells and provide novel insight
into the molecular mechanisms that underlie its apoptotic activity. Flavokawain B
exerts its apoptotic action through ROS generation and GADD153 up-regulation, which
lead to mitochondria-dependent apoptosis characterized by release of cytochrome c
and translocation of Bak. The up-regulation of GADD153 in flavokawain B-treated HCT116
cells is associated with mitochondrial dysfunction and altered expression of Bcl-2
family members. Moreover, pretreatment with the ROS scavenger N-acetylcysteine abolishes
flavokawain B-induced ROS generation, GADD153 up-regulation, and apoptosis. Similarly,
RNAi-mediated gene silencing reduced flavokawain B-enhanced expression of GADD153
and apoptotic Bim, leading to diminished apoptosis. Interestingly, flavokawain B provokes
G2/M accumulation as well as autophagy, in addition to apoptosis, suggesting that
multiple pathways are activated in flavokawain B-mediated anticancer activity. Taken
together, our data provide evidence for a molecular mechanism to explain the apoptotic
activity of Alpinia plants, showing that flavokawain B acts through ROS generation
and GADD153 up-regulation to regulate the expression of Bcl-2 family members, thereby
inducing mitochondrial dysfunction and apoptosis in HCT116 cells.
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