title: Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth.
abstract: OBJECTIVE
  Ecklonia cava is an abundant brown alga and has been reported to possess various bioactive compounds having anti-inflammatory effect. However, the anticancer effects of dieckol, a major active compound in E. cava, are poorly understood. In the present study, we investigated the anti-tumor activity of dieckol and its molecular mechanism in ovarian cancer cells and in a xenograft mouse model .
  
  
  METHODS
  MTT assay, PI staining, and PI and Annexin double staining were performed to study cell cytotoxicity, cell cycle distribution, and apoptosis. We also investigated reactive oxygen species (ROS) production and protein expression using flow cytometry and Western blot analysis, respectively. Anti-tumor effects of dieckol were evaluated in SKOV3 tumor xenograft model.
  
  
  RESULTS
  We found that the E. cava extract and its phlorotannins have cytotoxic effects on A2780 and SKOV3 ovarian cancer cells. Dieckol induced the apoptosis of SKOV3 cells and suppressed tumor growth without any significant adverse effect in the SKOV3-bearing mouse model. Dieckol triggered the activation of caspase-8, caspase-9, and caspase-3, and pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of dieckol. Furthermore, treatment with dieckol caused mitochondrial dysfunction and suppressed the levels of anti-apoptotic proteins. We further demonstrated that dieckol induced an increase in intracellular ROS, and the antioxidant N-acetyl-L-cysteine (NAC) significantly reversed the caspase activation, cytochrome c release, Bcl-2 downregulation, and apoptosis that were caused by dieckol. Moreover, dieckol inhibited the activity of AKT and p38, and overexpression of AKT and p38, at least in part, reversed dieckol-induced apoptosis in SKOV3 cells.
  
  
  CONCLUSIONS
  These data suggest that dieckol suppresses ovarian cancer cell growth by inducing caspase-dependent apoptosis via ROS production and the regulation of AKT and p38 signaling.
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ahn
authors.forename: Yeong-In
authors.initials: YI
authors.lastname: Yang
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000459:Phaeophyceae / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D001572:Benzofurans; D017382:Reactive Oxygen Species; C503840:dieckol; D020169:Caspases