title: The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma.
abstract: BACKGROUND
  Acacetin (5,7-dihydroxy-40-methoxyflavone), present in safflower seeds, plants, flowers, Cirisium rhinoceros Nakai, has been reported to be able to exert anti-peroxidative, anti-inflammatory, anti-plasmodial, and anti-proliferative activities by inducing apoptosis and blocking the progression of cell cycles.
  
  
  OBJECTIVE
  The objective of this study is to investigate the mechanism of acacetin-induced apoptosis of oral squamous cell carcinoma cell line (HSC-3).
  
  
  RESULTS
  Acacetin caused 50% growth inhibition (IC50) of HSC-3 cells at 25μg/mL over 24h in the MTT assay. Apoptosis was characterized by DNA fragmentation and increase of sub-G1 cells and involved activation of caspase-3 and PARP (poly-ADP-ribose polymerase). Maximum caspase-3 activity was observed with 100μg/mL of acacetin for 24h. Caspase-8 and -9 activation cascades mediated the activation of caspase-3. Acacetin caused reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c into the cytoplasm. Pretreatment with casapse-3 (Z-DEVD-FMK), -8 (Z-IETD-FMK), and 9 inhibitor (z-LEHD-fmk) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c. The mitogen-activated protein kinases (MAPKs) were activated by acacetin. Moreover, pretreating the cells with each of the caspase inhibitor or MAPKs specific inhibitors apparently inhibited acacetin-induced cytotoxicity of HSC-3 cells.
  
  
  CONCLUSIONS
  In conclusion, acacetin induce the apoptosis of oral squamous cell carcinoma cell line, which is closely related to its ability to activate the MAPK-mediated signaling pathways with the subsequent induction of a mitochondria- and caspase-dependent mechanism. These results strongly suggest that acacetin might have cancer inhibition and therapeutic potential.
authors.affiliation: Sychar Maxface Center for Maxillofacial Surgery, Seoul, South Korea.
authors.forename: Chae-Doo
authors.initials: CD
authors.lastname: Kim
authors.affiliation: Department of Natural Product Research, Institute of Jinan Red Ginseng, Jinan, South Korea.
authors.forename: Jeong-Dan
authors.initials: JD
authors.lastname: Cha
authors.affiliation: Nursing College, Yanbian University, China.
authors.forename: ShengJin
authors.initials: S
authors.lastname: Li
authors.affiliation: Oral Cancer Research Institute and Department of Oral & Maxillofacial Surgery, College of Dentistry, Yonsei University, Seoul, South Korea. Electronic address: cha8764@yuhs.ac.
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Cha
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D047309:Flavones / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047309:Flavones; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C023717:acacetin
keywords: Acacetin; Apoptosis; Caspases; Cell cycles; MAPKs signal pathway; Mitochondrial pathway; Oral cancer