title: Influence of hypoxia on TRAIL-induced apoptosis in tumor cells.
abstract: OBJECTIVE
  Tumor hypoxia reduces the efficacy of radiotherapy, many types of chemotherapy, and tumor necrosis factor-alpha (TNF-alpha). TRAIL (TNF-alpha-related apoptosis-inducing ligand) is a ligand for death receptors of the TNF superfamily shown to be selectively toxic for tumor cells and thereby a promising antineoplastic tool. The impact of hypoxia on TRAIL-induced apoptosis was examined in this study.
  
  
  METHODS
  Apoptosis induction and growth rates of various tumor cell lines under hypoxia were evaluated in vitro. Biologically effective induction of hypoxia was verified by determination of hypoxia-inducible factor-1 (HIF-1) activation. The efficacy of TRAIL- and radiation-induced apoptosis under different oxygen conditions was quantified in vitro. The impact of Bcl-2 on TRAIL-induced apoptosis under hypoxia or normoxia was evaluated by comparing cells expressing Bcl-2 with a vector control.
  
  
  RESULTS
  Moderate hypoxia caused no growth retardation or apoptosis, but led to activation of HIF-1 as a prerequisite of hypoxic gene induction. Cellular responses to TRAIL differed considerably among the cell lines tested. Hypoxia reduced radiation-induced, but not TRAIL-induced, apoptosis in the tested cell lines. Hypoxia did not induce Bcl-2 expression. Bcl-2 had a minor impact on the efficacy of TRAIL-induced apoptosis.
  
  
  CONCLUSIONS
  Taken together, the data indicate that TRAIL is clearly effective under conditions of proven hypoxia.
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Hoppe-Seylerstrasse 3, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weinmann
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marini
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.forename: Angelika
authors.initials: A
authors.lastname: Betsch
authors.forename: Barbara
authors.initials: B
authors.lastname: Goecke
authors.forename: Wilfried
authors.initials: W
authors.lastname: Budach
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019169:Jurkat Cells / Q000187:drug effects / Q000528:radiation effects; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases