Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis.
Topoisomerase I is an essential enzyme that relaxes DNA supercoiling by forming covalent DNA cleavage complexes, which are normally transient. Topoisomerase I-DNA complexes can be trapped by anticancer drugs (camptothecins) as well as by endogenous and exogenous DNA lesions. We show here that arsenic trioxide (a potent inducer of apoptosis that induces the intracellular accumulation of reactive oxygen species and targets mitochondria) induces cellular topoisomerase I cleavage complexes. Bcl-2 overexpression and quenching of reactive oxygen species, which prevent arsenic trioxide-induced apoptosis, also prevent the formation of topoisomerase I-DNA complexes, whereas enhancement of reactive oxygen species accumulation promotes these complexes. The caspase inhibitor, benzyloxycarbonyl-VAD partially prevents arsenic trioxide-induced topoisomerase I-DNA complexes and apoptosis, suggesting that activated caspases further maintain intracellular levels of reactive oxygen species that induce the formation of topoisomerase I-DNA complexes. Down-regulation of topoisomerase I expression decreases arsenic trioxide-induced apoptotic DNA fragmentation. Thus, we propose that arsenic trioxide induces topoisomerase I-DNA complexes that participate in chromatin fragmentation and programmed cell death during apoptosis.
Sordet
Olivier
O
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Liao
ZhiYong
Z
Liu
Hong
H
Antony
Smitha
S
Stevens
Ellen V
EV
Kohlhagen
Glenda
G
Fu
Haiqing
H
Pommier
Yves
Y
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D053938:DNA Fragmentation; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D007938:Leukemia; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019328:Buthionine Sulfoximine; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D000077237:Arsenic Trioxide