Comparison of anthracycline-induced death of human leukemia cells: programmed cell death versus necrosis.
We investigated the mode of cell death induced by the anthracyclines, aclarubicin, doxorubicin and daunorubicin in the human leukemia cell lines, HL60 and Jurkat. The cells were incubated with drug concentrations up to 500 nM for periods between 3 and 24 hours, followed by morphological and biochemical analyses. All three substances induced DNA fragmentation, evident as DNA laddering and appearance of cells with hypodiploid DNA content, externalization of phosphatidyl serine, activation of caspases and degradation of the apoptosis-specific endonuclease inhibitor DFF45. However, concentrations and times necessary for these effects to occur were different, aclarubicin being the quickest acting drug with a lag phase of 3 h, followed by daunorubicin with 6 h and doxorubicin with 24 h. More importantly, aclarubicin induced these effects while the cell membrane was intact, whereas doxorubicin and daunorubicin led to immediate loss of membrane integrity. Programmed cell death is characterised by preservation of membrane integrity in order to allow removal of apoptotic bodies, whereas cell rupture is an early event in necrosis. We therefore suggest that, in our experimental settings, doxorubicin- and daunorubicin-induced cell death occurs by necrosis, while aclarubicin induces programmed cell death.
Dartsch
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DC
Department of Toxicology, Hamburg University Medical School, Vogt-Koelln Str 30, 22527 Hamburg, Germany. polka@uke.uni-hamburg.de
Schaefer
A
A
Boldt
S
S
Kolch
W
W
Marquardt
H
H
D015250:Aclarubicin / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009336:Necrosis; D010718:Phosphatidylserines / Q000378:metabolism; D011506:Proteins / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D010718:Phosphatidylserines; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D015250:Aclarubicin; D004317:Doxorubicin; D020169:Caspases; D003630:Daunorubicin