title: Flavokawain B inhibits growth of human squamous carcinoma cells: Involvement of apoptosis and cell cycle dysregulation in vitro and in vivo.
abstract: Flavokawain B is a natural chalcone isolated from the rhizomes of Alpenia pricei Hayata. In the present study, we have investigated the antiproliferative and apoptotic effect of flavokawain B (5-20 μg/ml; 17.6-70.4 μM) against human squamous carcinoma (KB) cells. Exposure of KB cells with flavokawain B resulted in apoptosis, evidenced by loss of cell viability, profound morphological changes, genomic DNA fragmentation and sub-G1 phase accumulation. Apoptosis induced by flavokawain B results in activation of caspase-9, -3 and -8, cleavage of poly ADP ribose polymerase (PARP) and Bid in KB cells. Flavokawain B also down-regulate Bcl-2 with concomitant increase in Bax level, which resulted in release of cytochrome c. Taken together, the induction of apoptosis by flavokawain B involved in both death receptor and mitochondrial pathway. We also observed that flavokawain B caused the G2/M phase arrest that was mediated through reductions in the levels of cyclin A, cyclin B1, Cdc2 and Cdc25C and increases in p21/WAF1, Wee1 and p53 levels. Moreover, flavokawain B significantly inhibits matrix metalloproteinase-9 and urokinase plasminogen activator expression, whereas tissue inhibitor of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 were increased, which are playing critical role in tumor metastasis. In addition, flavokawain B treatment significantly inhibited in vivo growth of human KB cell-derived tumor xenografts in nude mice, which is evidenced by augmentation of apoptotic DNA fragmentation, as detected by in situ terminal deoxynucleotidyl transferase-meditated dUTP nick end-labeling staining. The induction of cell cycle arrest and apoptosis by flavokawain B may provide a pivotal mechanism for its cancer chemopreventive action.
authors.affiliation: Department of Food Science and Technology, Central Taiwan University of Science and Tachnology, Taichung 40402, Taiwan.
authors.forename: Elong
authors.initials: E
authors.lastname: Lin
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Lin
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wang
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Chen
authors.forename: Jiuun-Wang
authors.initials: JW
authors.lastname: Liao
authors.forename: Hsueh-Wei
authors.initials: HW
authors.lastname: Chang
authors.forename: Ssu-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Lin
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Yang
authors.forename: You-Cheng
authors.initials: YC
authors.lastname: Hseu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D005419:Flavonoids; D051028:bcl-2-Associated X Protein; C452039:flavokawain B; D002599:Chalcone; D045304:Cytochromes c; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D014568:Urokinase-Type Plasminogen Activator; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1