The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation.
Some widely used antidepressants such as imipramine, clomipramine, and citalopram have been found to possess antineoplastic effects. In the present study, these compounds were found to induce apoptotic cell death in human acute myeloid leukemia HL-60 cells. Apoptosis induced by the antidepressants was identified by electron microscopy and conventional agarose gel electrophoresis and was quantitated by propodium iodide staining and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) via flow cytometry. Treatment with apoptosis-inducing concentrations of the antidepressants (80 microM imipramine, 35 microM clomipramine, or 220 microM citalopram) caused induction of caspase-3/caspase-3-like activity, which was monitored by the cleavage of poly(ADP-ribose) polymerase (PARP), the loss of the 32 kD caspase-3 (CPP32) precursor, and the cleavage of the fluorescent CPP32-like substrate PhiPhiLux. Pretreatment with a potent caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (zVAD-fmk) inhibited antidepressant-induced CPP32/CPP32-like activity and apoptosis. Furthermore, activation of caspase induced by the antidepressants was preceded by the hypergeneration of intracellular reactive oxygen species (ROS). These results suggested that the antidepressants may induce apoptosis via a caspase-3-dependent pathway, and induction of apoptosis by the antidepressants may provide a clue for the mechanism of their antineoplastic effects.
Xia
Z
Z
Department of Biochemistry, Wallenberg Laboratory, Stockholm University, Sweden. xia@tuborg.biokemi.su.se
Bergstrand
A
A
DePierre
J W
JW
Nässberger
L
L
D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000928:Antidepressive Agents; D017382:Reactive Oxygen Species; D015283:Citalopram; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002997:Clomipramine; D007099:Imipramine