Topoisomerase II and tubulin inhibitors both induce the formation of apoptotic topoisomerase I cleavage complexes.
Topoisomerase I (Top1) is a ubiquitous enzyme that removes DNA supercoiling generated during transcription and replication. Top1 can be trapped on DNA as cleavage complexes by the anticancer drugs referred to as Top1 inhibitors as well as by alterations of the DNA structure. We reported recently that Top1 cleavage complexes (Top1cc) are trapped during apoptosis induced by arsenic trioxide and staurosporine. In the present study, we generalize the occurrence of apoptotic Top1cc in response to anticancer drugs, which by themselves do not directly interact with Top1: the topoisomerase II inhibitors etoposide, doxorubicin, and amsacrine, and the tubulin inhibitors vinblastine and Taxol. In all cases, the Top1cc form in the early phase of apoptosis and persist throughout the apoptotic process. Their formation is prevented by the caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone and the antioxidant N-acetyl-L-cysteine. We propose that the trapping of Top1cc is a general process of programmed cell death, which is caused by alterations of the DNA structure (oxidized bases and strand breaks) induced by caspases and reactive oxygen species.
Sordet
Olivier
O
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 5068, Bethesda, MD 20892-4255, USA.
Goldman
Abby
A
Pommier
Yves
Y
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000677:Amsacrine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000677:Amsacrine; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D017239:Paclitaxel