Inhibition of both etoposide-induced DNA fragmentation and activation of poly(ADP-ribose) synthesis by zinc ion.
Treatment of a human promyelocytic leukemia cell line (HL-60) with etoposide for 3-4 hrs produced an extensive degradation of DNA. Agarose gel electrophoresis showed DNA fragmentation in a nucleosomal ladder pattern. Simultaneous addition of zinc ion (ZnSO4, 1 mM) inhibited DNA fragmentation, although the amount of DNA strand breakage introduced initially by etoposide did not change significantly as measured by the DNA unwinding assay. Furthermore, zinc ion abrogated both the activation of poly(ADP-ribose) synthesis and the morphologic changes characteristic of apoptosis by etoposide. These results suggest that zinc ion inhibits a metabolic process somewhere between initial DNA cleavage through an interference with type II topoisomerase and delayed degradation of cellular DNA to a nucleosome-like pattern.
Shimizu
T
T
Department of Pediatrics, Faculty of Medicine, Kyoto University, Japan.
Kubota
M
M
Tanizawa
A
A
Sano
H
H
Kasai
Y
Y
Hashimoto
H
H
Akiyama
Y
Y
Mikawa
H
H
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D005047:Etoposide / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008769:Methylnitronitrosoguanidine; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology*
D004273:DNA, Neoplasm; D009702:Nucleoside Diphosphate Sugars; D059005:Topoisomerase II Inhibitors; D008769:Methylnitronitrosoguanidine; D011064:Poly Adenosine Diphosphate Ribose; D005047:Etoposide; D015032:Zinc