Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X(L).
In order to investigate the molecular mechanism of the antineoplastic effects exerted by the antidepressive agents imipramine, clomipramine, and citalopram, we examined the effects of these compounds on cell viability, generation of reactive oxygen species (ROS), and mitochondrial membrane potential (DeltaPsi(m)) in human acute myeloid leukemia HL-60 cells. Our results indicate that exposure to these compounds causes a loss in cell viability by activating the apoptotic process, as identified by electron microscopy, DNA gel electrophoresis, and flow cytometry. The increased generation of ROS induced by these drugs was a relatively early event and preceded the loss of DeltaPsi(m). Overexpression of the antiapoptotic protein Bcl-2 or Bcl-X(L) prevents antidepressant-induced apoptosis, as well as loss of DeltaPsi(m), but does not affect the generation of ROS.
Unit for Biochemical Toxicology, Department of Biochemistry, Stockholm University, S-106 91, Stockholm, Sweden. xia@tuborg.biokemi.su.se
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Z
Xia
B
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Lundgren
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Bergstrand
J W
JW
DePierre
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Nässberger
D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection; D051020:bcl-X Protein
D000928:Antidepressive Agents; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D015283:Citalopram; D002997:Clomipramine; D007099:Imipramine