Induction of apoptosis in human cancer cell lines by the novel anthracenyl-amino acid topoisomerase I inhibitor NU/ICRF 505.
Anthracenyl-amino acid conjugates represent a novel chemical class of topoisomerase (topo) inhibitor. NU/ICRF 505 is a lead compound that stabilises topo I cleavable complexes and is actively cytotoxic at low microM concentrations. In this study, endonucleolytic DNA cleavage was used as a marker of apoptosis to investigate mechanisms of cell death produced by this compound. NU/ICRF 505 (5 microM) induced a substantial increase in the level of DNA fragmentation in HL60 cells (up to 30% of total extracted DNA) but only after a 48 and 72 h drug exposure (compared with 6 h after treatment with camptothecin), as determined qualitatively by conventional gel electrophoresis and quantitatively by spectrofluorimetry. This effect was substantially reversed by co-treatment with zinc (1 mM). Subsequent studies with the human lung (NX002), ovarian (A2780) and colon (HT29) cancer cell lines yielded evidence of formation of higher molecular weight DNA fragments in NX002 and A2780 cells in response to NU/ICRF 505 (5 microM). Co-treatment with zinc (1 mM) caused a small decrease in DNA fragmentation. These data suggest that the induction of apoptosis may play an important role in the mechanism of cytotoxicity of NU/ICRF 505 in HL60 cells and that other pathways of cell death may also be operative in NX002 and A2780 in conjunction with apoptosis.
Meikle
I
I
Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
Cummings
J
J
Macpherson
J S
JS
Smyth
J F
JF
D000880:Anthraquinones / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
D000880:Anthraquinones; D004791:Enzyme Inhibitors; C100645:NU-ICRF 505; D059004:Topoisomerase I Inhibitors; D014443:Tyrosine; D004247:DNA; D015032:Zinc