Flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent apoptotic activity: Involvement of ROS and GADD153 upstream of mitochondria-dependent apoptosis in HCT116 cells.
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.
Kuo
Yu-Feng
YF
Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
Su
Ying-Zhen
YZ
Tseng
Yen-Hsueh
YH
Wang
Sheng-Yang
SY
Wang
Hsi-Ming
HM
Chueh
Pin Ju
PJ
D032429:Alpinia; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D008516:Medicine, Chinese Traditional; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C452039:flavokawain B; D051742:Transcription Factor CHOP; D045304:Cytochromes c