The chalcone flavokawain B induces G2/M cell-cycle arrest and apoptosis in human oral carcinoma HSC-3 cells through the intracellular ROS generation and downregulation of the Akt/p38 MAPK signaling pathway.
Chalcones have been described to represent cancer chemopreventive food components that are rich in fruits and vegetables. In this study, we examined the anti-oral cancer effect of flavokawain B (FKB), a naturally occurring chalcone isolated from Alpinia pricei (shell gingers), and revealed its molecular mechanism of action. Treatment of human oral carcinoma (HSC-3) cells with FKB (1.25-10 μg/mL; 4.4-35.2 μM) inhibited cell viability and caused G(2)/M arrest through reductions in cyclin A/B1, Cdc2, and Cdc25C levels. Moreover, FKB treatment resulted in the induction of apoptosis, which was associated with DNA fragmentation, mitochondria dysfunction, cytochrome c and AIF release, caspase-3 and caspase-9 activation, and Bcl-2/Bax dysregulation. Furthermore, increased Fas activity and procaspase-8, procaspase-4, and procaspase-12 cleavages were accompanied by death receptor and ER-stress, indicating the involvement of mitochondria, death-receptor, and ER-stress signaling pathways. FKB induces apoptosis through ROS generation as evidenced by the upregulation of oxidative-stress markers HO-1/Nrf2. This mechanism was further confirmed by the finding that the antioxidant N-acetylcysteine (NAC) significantly blocked ROS generation and consequently inhibited FKB-induced apoptosis. Moreover, FKB downregulated the phosphorylation of Akt and p38 MAPK, while their inhibitors LY294002 and SB203580, respectively, induced G(2)/M arrest and apoptosis. The profound reduction in cell number was observed in combination treatment with FKB and Akt/p38 MAPK inhibitors, indicating that the disruption of Akt and p38 MAPK cascades plays a functional role in FKB-induced G(2)/M arrest and apoptosis in HSC-3 cells.
Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung, Taiwan.
You-Cheng
YC
Hseu
Meng-Shiou
MS
Lee
Chi-Rei
CR
Wu
Hsin-Ju
HJ
Cho
Kai-Yuan
KY
Lin
Guan-Hua
GH
Lai
Sheng-Yang
SY
Wang
Yueh-Hsiung
YH
Kuo
K J Senthil
KJ
Kumar
Hsin-Ling
HL
Yang
D016588:Anticarcinogenic Agents; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology; D015536:Down-Regulation; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009062:Mouth Neoplasms / Q000473:pathology* / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D047188:Chalcones; D005419:Flavonoids; D017382:Reactive Oxygen Species; C452039:flavokawain B