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