Mitochondrial-targeted fatty acid analog induces apoptosis with selective loss of mitochondrial glutathione in promyelocytic leukemia cells.
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.
Tronstad
Karl Johan
KJ
Section of Medical Biochemistry, Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
Gjertsen
Bjørn Tore
BT
Krakstad
Camilla
C
Berge
Kjetil
K
Brustugun
Odd Terje
OT
Døskeland
Stein Ove
SO
Berge
Rolf Kristian
RK
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
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