title: Docosahexaenoic acid induces apoptosis in MCF-7 cells in vitro and in vivo via reactive oxygen species formation and caspase 8 activation.
abstract: BACKGROUND
  The present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA), with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions.
  
  
  RESULTS
  In vitro studies showed that DHA strongly reduces the viability and DNA synthesis of MCF-7 human breast cancer cells in culture, and also promotes cell death via apoptosis. Mechanistically, accumulation of reactive oxygen species and activation of caspase 8 contribute critically to the induction of apoptotic cell death. Co-presence of antioxidants or selective inhibition or knockdown of caspase 8 each effectively abrogates the cytotoxic effect of DHA. Using athymic nude mice as an in vivo model, we found that feeding animals the 5% fish oil-supplemented diet for 6 weeks significantly reduces the growth of MCF-7 human breast cancer cells in vivo through inhibition of cancer cell proliferation as well as promotion of cell death. Using 3-nitrotyrosine as a parameter, we confirmed that the fish oil-supplemented diet significantly increases oxidative stress in tumor cells in vivo. Analysis of fatty acid content in plasma and tissues showed that feeding animals a 5% fish oil diet increases the levels of DHA and eicosapentaenoic acid in both normal and tumorous mammary tissues by 329% and 300%, respectively.
  
  
  CONCLUSIONS
  DHA can strongly induce apoptosis in human MCF-7 breast cancer cells both in vitro and in vivo. The induction of apoptosis in these cells is selectively mediated via caspase 8 activation. These observations call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of human breast cancer.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Ki Sung
authors.initials: KS
authors.lastname: Kang
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukui
authors.forename: Taylor
authors.initials: T
authors.lastname: Jay
authors.forename: Bao Ting
authors.initials: BT
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D005260:Female; D005395:Fish Oils / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D053181:Caspase 8