title: Mitochondrial-targeted fatty acid analog induces apoptosis with selective loss of mitochondrial glutathione in promyelocytic leukemia cells.
abstract: Some fatty acids and derivatives are known to induce cell death in cancer cells. Mitochondria may have important roles in the death process. Therefore, we investigated the mitochondrial contribution in cell death induced by a modified fatty acid, tetradecylthioacetic acid (TTA), which cannot be beta-oxidized. TTA treatment induced apoptosis in IPC-81 leukemia cells via depolarization of the mitochondrial membrane potential (deltapsi) and early release of cytochrome c, accompanied by depletion of mitochondrial glutathione. Caspase-3 activation and cleavage of poly (ADP-ribose) polymerase (PARP) occurred at a late stage, but the broad-spectra caspase inhibitor zVAD-fmk did not block TTA-induced apoptosis. Overexpression of Bcl-2 partially prevented TTA-induced apoptosis, whereas cAMP-induced cell death was completely blocked. In conclusion, TTA seems to trigger apoptosis through mitochondrial-mediated mechanisms and selective modulation of the mitochondrial redox equilibrium.
authors.affiliation: Section of Medical Biochemistry, Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: Karl Johan
authors.initials: KJ
authors.lastname: Tronstad
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.forename: Kjetil
authors.initials: K
authors.lastname: Berge
authors.forename: Odd Terje
authors.initials: OT
authors.lastname: Brustugun
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
authors.forename: Rolf Kristian
authors.initials: RK
authors.lastname: Berge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007118:Immunoassay; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D013440:Sulfides; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C062078:1-(carboxymethylthio)tetradecane; D045304:Cytochromes c; D000242:Cyclic AMP; D020169:Caspases; D005978:Glutathione