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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.

Abstract
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.
AuthorsYou-Cheng Hseu, Meng-Shiou Lee, Chi-Rei Wu, Hsin-Ju Cho, Kai-Yuan Lin, Guan-Hua Lai, Sheng-Yang Wang, Yueh-Hsiung Kuo, K J Senthil Kumar, Hsin-Ling Yang
JournalJournal of agricultural and food chemistry (J Agric Food Chem) Vol. 60 Issue 9 Pg. 2385-97 (Mar 07 2012) ISSN: 1520-5118 [Electronic] United States
PMID22324429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticarcinogenic Agents
  • Chalcones
  • Flavonoids
  • Reactive Oxygen Species
  • flavokawain B
Topics
  • Anticarcinogenic Agents
  • Apoptosis (drug effects)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Chalcones (pharmacology)
  • Down-Regulation
  • Flavonoids (pharmacology)
  • Humans
  • MAP Kinase Signaling System (drug effects, physiology)
  • Mouth Neoplasms (pathology, prevention & control)
  • Reactive Oxygen Species (metabolism)

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