title: Camptothecin and khat (Catha edulis Forsk.) induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines.
abstract: BACKGROUND
  An organic extract of the recreational herb khat (Catha edulis Forsk.) triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.
  
  
  RESULTS
  Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation.
  
  
  CONCLUSIONS
  Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.
authors.affiliation: The Gade Institute, University of Bergen, Bergen, Norway.
authors.forename: Therese
authors.initials: T
authors.lastname: Bredholt
authors.forename: Elizabeth Ao
authors.initials: EA
authors.lastname: Dimba
authors.forename: Hanne R
authors.initials: HR
authors.lastname: Hagland
authors.forename: Line
authors.initials: L
authors.lastname: Wergeland
authors.forename: Jørn
authors.initials: J
authors.lastname: Skavland
authors.forename: Kjell O
authors.initials: KO
authors.lastname: Fossan
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Tronstad
authors.forename: Anne C
authors.initials: AC
authors.lastname: Johannessen
authors.forename: Olav K
authors.initials: OK
authors.lastname: Vintermyr
authors.forename: Bjørn T
authors.initials: BT
authors.lastname: Gjertsen
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D029754:Catha / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010641:Phenotype; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; D002166:Camptothecin